Clinical trial NCT04308304
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease Donepezil
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-02-16; Completion date: 2022-05-18
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study investigated the effects on safety and pharmacokinetics (PK) of MK-1942 and donepezil when co-administered to participants with Alzheimer's Disease with mild-to-moderate cognitive impairment stably treated with donepezil. The objectives of this study were to determine if the combination of MK-1942 with donepezil increases the incidence or severity of adverse events (AEs) previously reported for these agents alone, or results in unanticipated AEs in the patient population targeted for MK-1942 treatment. In addition, changes in the PK parameters of either MK-1942 or donepezil as a result of co-administration were assessed.

Detailed description:

Arms: arm 1: Participants receive Dose Level 1: 8-mg MK-1942 twice daily (BID) x 7 days (7D), Day 1 to Day 7; Dose Level 2: 15-mg MK-1942 BID x 7D, Day 8 to Day 14; Dose Level 3: 30-mg MK-1942 BID x 7D, Day 15 to Day 21; Dose Level 4: ≤50-mg MK-1942 BID x 7D (Provisional Dose Level), Day 22 to Day 28 All participants to receive Donepezil once daily. arm 2: Placebo to MK-1942 BID x 21 \[28\] D All participants to receive Donepezil once daily.
Interventions: intervention 1: MK-1942 intervention 2: Donepezil intervention 3: Placebo
Intervention descriptions: intervention 1: MK-1942 1 mg, 5 mg, and/or 10 mg capsules taken twice daily (BID) by mouth. intervention 2: Donepezil 5 mg and/or 10 mg tablets taken once daily (QD) by mouth. intervention 3: Placebo capsule matched to MK-1942 taken BID by mouth.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT04308304
Document Date:           16-Mar-2020
A Randomized, Double-Blind, Placebo-
Controlled Study of the Safety and 
Pharmacokinetics of MK-1942 Administered to 
Alzheimer’s Disease Patients Receiving 
Donepezil Treatment


PRODUCT: MK-1942  
1
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and 
Pharmacokinetics of MK-1942 Administered to Alzheimer’s Disease Patients Receiving 
Donepezil Treatment.
Protocol Number: 005-01
Compound Number: MK-1942
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
139557
Approval Date:   16 March 2020
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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 01
16-MAR-2020
Correction of NIMP designation of donepezil was required to ensure proper 
safety reporting to regulatory agency. Other editorial changes were 
implemented and information on the ongoing P004 was updated.
Original Protocol
10-JAN-2020
Not Applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: MK-1942-005-01
Overall Rationale for the Amendments:
Correction of NIMP designation of donepezil was required to ensure proper safety reporting to regulatory agency. Other editorial 
changes were implemented and information on the ongoing P004 was updated.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities
Remove 24hr timepoint from footnote “m”
24hr timepoint overlapped with the pre-dose measurement 
on the following day. Removing this timepoint eliminated 
the redundant timepoint.
Section 2.2.3.2 MK-1942-
004
Added dosing and safety data up to Panel 
B in P004. 
Ensure protocol has the most recent information on the 
safety and tolerability of MK-1942 in study P004 as of the 
time of this amendment.
Section 5.2 Exclusion 
Criteria
Exclusion #10 – removed text below
“Is unable to refrain from or anticipates the 
use of any medication, including 
prescription and non-prescription drugs or 
herbal remedies (see Section 6.5, item 8 for 
specific examples), beginning 
approximately 2 weeks (or 5 half-lives) 
prior to administration of the initial dose of 
study drug, throughout the study (including 
intervals between treatment periods), until 
the post-study visit. There may be certain 
medications that are permitted (see Section 
6.5).”
PN005 is being conducted in an elderly population likely to 
be taking prescription medications for chronic conditions.  
The highlighted section causes confusion around those 
medications that are permitted in the study. In order to 
ensure clarity around which concomitant medications are 
permitted in candidates for enrollment and under what 
conditions, this section was removed.  The remaining text 
in Exclusion criteria 10 states “All medications being taken 
by candidates for enrollment in the study should be 
reviewed by the PI and the Sponsor to determine their 
propensity for altering MK-1942 exposure, or for MK-1942 
to interfere with the metabolism of the medication. 
Medications prescribed for the candidate that are stably 
treating a condition should not be interrupted.  
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Section # and Name
Description of Change 
Brief Rationale 
Section 6.1 Study 
Interventions 
Administered, Table 7
Changed donepezil designation from 
Investigational Medicinal Product (IMP) to 
Non-Investigational Medicinal Product 
(NIMP).
Donepezil was incorrectly labeled as IMP. Correction was 
needed to ensure proper safety reporting. 
Section 6.5 Concomitant 
Therapy
Removed felbamate, topiramate, 
probenecid, lamotrigine and riluzole from 
the list of prohibited concomitant 
medications
New pre-clinical data suggest that the potential for a DDIs 
with these drugs is low. 
Section 8.10.5 Critical 
Procedures Based on 
Study Objectives: Timing 
of Procedure
Predose safety standard safety evaluations: 
Added that windows are prior to dosing. 
Changed ECG window from 3hrs to 1 hr 
prior to dosing. 
Editorial change to ensure clarity of interpretation. 
ECG window narrowed to ensure it is as close to dosing as 
possible. 
Sections 4.2.1.3 Future 
Biomedical Research, 
8.1.1.2 Consent and 
Collection of Specimens 
for Future Biomedical 
Research and Appendix 
10.6 Collection and 
Management of 
Specimens for Future 
Biomedical Research
Removal of the word “substudy”
New template requirement
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................23
2.2.1
Pharmaceutical and Therapeutic Background .............................................23
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.2.3
Ongoing Clinical Studies.............................................................................23
2.2.3.1
MK-1942-002: A Double-Blind, Placebo-Controlled, Multiple 
Ascending Dose Study of the Safety, Tolerability and 
Pharmacokinetics of MK-1942 in Healthy Participants ....................23
2.2.3.2
MK-1942-004: A Randomized, Double Blind, Placebo-
Controlled Investigation of the Safety, Tolerability and 
Pharmacokinetics of Multiple-Dose Regimens of MK-1942 in 
Healthy Elderly Participants ..............................................................37
2.2.4
Information on Other Study-related Therapy ..............................................38
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................39
4
STUDY DESIGN............................................................................................................40
4.1
Overall Design......................................................................................................40
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Safety Endpoints................................................................................42
Pharmacokinetic Endpoints ...................................................................................43
4.2.1.2
Planned Exploratory Biomarker Research.........................................44
4.2.1.2.1
Planned Genetic Analysis ........................................................44
4.2.1.3
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator/Placebo .............................................45
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................45
4.3
Justification for Dose...........................................................................................45
4.3.1
Starting Dose for This Study........................................................................45
4.3.2
Maximum Dose/Exposure for This Study ...................................................46
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4.3.3
Rationale for Dose Interval and Study Design ............................................47
4.4
Beginning and End of Study Definition .............................................................48
4.4.1
Clinical Criteria for Early Study Termination .............................................48
5
STUDY POPULATION ................................................................................................49
5.1
Inclusion Criteria.................................................................................................49
5.2
Exclusion Criteria................................................................................................51
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
5.3.1.1
Diet Restrictions.................................................................................54
5.3.1.2
Fruit Juice Restrictions ......................................................................54
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................54
5.3.2.1
Caffeine Restrictions..........................................................................54
5.3.2.2
Alcohol Restrictions...........................................................................55
5.3.2.3
Tobacco Restrictions..........................................................................55
5.3.3
Activity Restrictions ....................................................................................55
5.4
Screen Failures.....................................................................................................55
5.5
Participant Replacement Strategy......................................................................55
6
STUDY INTERVENTION............................................................................................56
6.1
Study Intervention(s) Administered...................................................................56
6.2
Preparation/Handling/Storage/Accountability .................................................58
6.2.1
Dose Preparation..........................................................................................58
6.2.2
Handling, Storage, and Accountability........................................................58
6.3
Measures to Minimize Bias: Randomization and Blinding..............................59
6.3.1
Intervention Assignment..............................................................................59
6.3.2
Stratification.................................................................................................59
6.3.3
Blinding........................................................................................................59
6.4
Study Intervention Compliance..........................................................................59
6.5
Concomitant Therapy..........................................................................................59
6.5.1
Rescue Medications and Supportive Care ...................................................61
6.6
Dose Modification (Escalation/Titration/Other)...............................................61
6.6.1
Stopping Rules.............................................................................................61
6.6.2
Dizziness/Nausea Stopping Criteria ............................................................61
6.7
Intervention After the End of the Study............................................................63
6.8
Clinical Supplies Disclosure................................................................................63
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................63
7.1
Discontinuation of Study Intervention...............................................................63
7.2
Participant Withdrawal From the Study...........................................................64
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7.3
Lost to Follow-up .................................................................................................65
8
STUDY ASSESSMENTS AND PROCEDURES........................................................65
8.1
Administrative and General Procedures ...........................................................66
8.1.1
Informed Consent.........................................................................................66
8.1.1.1
General Informed Consent.................................................................66
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................67
8.1.2
Inclusion/Exclusion Criteria ........................................................................67
8.1.3
Participant Identification Card.....................................................................67
8.1.4
Medical History ...........................................................................................68
8.1.5
Prior and Concomitant Medications Review...............................................68
8.1.5.1
Prior Medications...............................................................................68
8.1.5.2
Concomitant Medications..................................................................68
8.1.6
Assignment of Screening Number...............................................................68
8.1.7
Assignment of Treatment/Randomization Number.....................................68
8.1.8
Study Intervention Administration ..............................................................69
8.1.8.1
Timing of Dose Administration.........................................................69
8.1.9
Discontinuation and Withdrawal .................................................................69
8.1.9.1
Withdrawal From Future Biomedical Research ................................70
8.1.10
Participant Blinding/Unblinding..................................................................70
8.1.11
Domiciling ...................................................................................................71
8.1.12
Calibration of Equipment.............................................................................71
8.2
Efficacy/Immunogenicity Assessments ..............................................................71
8.3
Safety Assessments...............................................................................................71
8.3.1
Physical Examinations.................................................................................72
8.3.2
Vital Signs....................................................................................................72
8.3.2.1
Resting Vital Signs ............................................................................72
8.3.2.2
Orthostatic Vital Signs.......................................................................73
8.3.3
Electrocardiograms ......................................................................................73
8.3.4
Neurological Exams.....................................................................................74
8.3.5
Mini-Mental State Examination (MMSE-2)................................................74
8.3.6
WAIS-R Digit Symbol Substitution Test (DSST).......................................74
8.3.7
Clinical Safety Laboratory Assessments .....................................................74
8.3.8
Suicidal Ideation and Behavior Monitoring.................................................75
8.3.8.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................75
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................75
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................76
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......78
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...78
8.4.4
Regulatory Reporting Requirements for SAE .............................................78
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................78
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................78
8.4.7
Events of Clinical Interest............................................................................78
8.5
Treatment of Overdose........................................................................................79
8.6
Pharmacokinetics.................................................................................................79
8.6.1
Blood Collection for Plasma MK-1942 .......................................................79
8.7
Pharmacodynamics..............................................................................................80
8.8
Biomarkers ...........................................................................................................80
8.8.1
Planned Genetic Analysis Sample Collection..............................................80
8.9
Future Biomedical Research Sample Collection...............................................80
8.10
Visit Requirements...............................................................................................80
8.10.1
Screening......................................................................................................80
8.10.2
Treatment Period Visit.................................................................................81
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........81
8.10.4
Poststudy......................................................................................................81
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure .......81
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................82
9
STATISTICAL ANALYSIS PLAN .............................................................................83
9.1
Statistical Analysis Plan Summary.....................................................................84
9.2
Responsibility for Analyses.................................................................................85
9.3
Hypotheses/Estimation ........................................................................................86
9.4
Analysis Endpoints...............................................................................................86
9.5
Analysis Populations............................................................................................86
9.6
Statistical Methods...............................................................................................87
9.6.1
Safety ...........................................................................................................87
9.6.2
Pharmacokinetics .........................................................................................87
9.6.3
General.........................................................................................................89
9.7
Interim Analyses ..................................................................................................89
9.8
Multiplicity ...........................................................................................................89
9.9
Sample Size and Power Calculations .................................................................90
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................91
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10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........91
10.1.1
Code of Conduct for Clinical Trials.............................................................91
10.1.2
Financial Disclosure.....................................................................................93
10.1.3
Data Protection.............................................................................................93
10.1.3.1
Confidentiality of Data ......................................................................94
10.1.3.2
Confidentiality of Participant Records...............................................94
10.1.3.3
Confidentiality of IRB/IEC Information............................................94
10.1.4
Publication Policy........................................................................................94
10.1.5
Compliance with Study Registration and Results Posting Requirements ...95
10.1.6
Compliance with Law, Audit, and Debarment ............................................95
10.1.7
Data Quality Assurance ...............................................................................96
10.1.8
Source Documents .......................................................................................97
10.1.9
Study and Site Closure.................................................................................97
10.2
Appendix 2: Clinical Laboratory Tests..............................................................98
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................99
10.3.1
Definition of AE ..........................................................................................99
10.3.2
Definition of SAE ......................................................................................100
10.3.3
Additional Events Reported.......................................................................101
10.3.4
Recording AE and SAE .............................................................................101
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................105
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................106
10.5
Appendix 5: Contraceptive Guidance..............................................................107
10.5.1
Definitions..................................................................................................107
10.5.2
Contraception Requirements......................................................................108
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................109
10.7
Appendix 7: Country-specific Requirements..................................................114
10.8
Appendix 8: Approximate Blood Volume Table.............................................115
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................116
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...118
10.11 Appendix 11: The General and Targeted Neurological Exams.....................119
10.12 Appendix 12: Additional Information to be Collected from Subjects Who 
Report Suicidal Ideation and/or Behavior.......................................................125
10.13 Appendix 13: Abbreviations .............................................................................126
11
REFERENCES.............................................................................................................128
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LIST OF TABLES
Table 1
Proposed Dosing Regimens of MK-1942 and Donepezil for the Study ...........16
Table 2
Summary of the Pharmacokinetic Parameters of MK-1942 Following 
Administration of Multiple Ascending Oral Doses to Healthy Adult 
Subjects .............................................................................................................25
Table 3
Subjects Reporting Adverse Events (Incidence > 0% in One or More 
Treatment Groups) ............................................................................................30
Table 4
Calculated 
 on the Last Day of Each Dose 
Level Following Treatment of Healthy Adult Participants with Oral Doses 
of MK-1942 in Panel B .....................................................................................37
Table 5
Proposed Dosing Regimens for MK-1942-004-001 .........................................38
Table 6
Projected Systemic Exposures and Receptor Occupancies Achieved at 
Steady State with the Proposed Dose Levels. ...................................................46
Table 7
Study Interventions............................................................................................57
Table 8
Sample Allocation Schedule .............................................................................59
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ..................................................................................77
Table 10 Pharmacokinetic Sample (Blood) Collection Windows....................................82
Table 11 Operating Characteristics for a One AE Incidence Rate...................................90
Table 12 Protocol-required Safety Laboratory Assessments ...........................................98
CCI
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LIST OF FIGURES
Figure 1 Timing of Monitoring and Interventions...........................................................17
Figure 2 Mean (SD) Plasma Concentration Time Profiles for MK-1942 Following 
Administration of Multiple Oral Doses to Healthy Adult Subjects in Panels 
E and F (red) from Study MK-1942-002. (Top; Linear Scale, Bottom; Log-
linear Scale).......................................................................................................28
Figure 3 Amelioration of Scopolamine-Induced Cognitive Impairment by an 
...................................................................................................46
CCI
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and 
Pharmacokinetics of MK-1942 Administered to Alzheimer’s Disease Patients Receiving 
Donepezil Treatment.
Short Title: MK-1942/Donepezil Interactions in AD Patients
Acronym: DDI
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population consists of Alzheimer Disease (AD) patients with mild to moderate 
cognitive impairment, 50-85 years of age. 
Primary Objectives
Primary Endpoints
- Evaluate the safety and tolerability of 
treatment (MK-1942 co-administered with 
donepezil) in AD patients with mild-to-
moderate cognitive impairment. 
- Safety measures (VS, ECGs, clinical 
chemistry, hematology, urinalysis, targeted 
neurological exams, Columbia suicide 
severity rating scale) and Adverse Event 
reports
Secondary Objectives
Secondary Endpoints
- Evaluate the effects of donepezil on the PK 
of MK-1942 in AD patients
Hypothesis
- The plasma Cmax of MK-1942 determined 
on the last day of a titrated treatment regimen 
(Day 21 [28]) when co-administered with 
donepezil to AD patients is similar to the 
Cmax obtained following administration of 
MK-1942 to HEV from MK-1942-004, Panel 
C. That is, the true GMR (MK-1942 + 
donepezil in AD / MK-1942 in HEV) is 
contained within the interval (0.5, 2.0).
- Evaluate the effects of MK-1942 on the PK 
of donepezil in AD patients. 
Estimation: 
- Estimate the GMRs of plasma PK 
parameters (AUC0-24, Cmax) for donepezil 
before and during administration of donepezil 
+ MK-1942 to AD patients.
- Cmax, AUC0-12, AUC0-24, Ctrough, 
Tmax, apparent terminal t1/2, CLss/F, and 
Vzss/F of MK-1942
- AUC0-24, Cmax, Ctrough, Tmax for 
donepezil
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Alzheimer Disease
Population
AD patients with mild-to-moderate cognitive impairment
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 24 weeks from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 24 participants will be allocated/randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis--
tration
Regimen/
Treatment Period
Use
AD Patients
MK-1942
1-mg, 
5-mg, 
10-mg
BID
PO
8-mg BID x 7D; 
15-mg BID x 7D; 
30-mg BID x 7 D;
50-mg BID x 7D 
(provisional)
Ex-
perimen-
tal
MK-1942 
Placebo
N/A
BID
PO
BID x 21 (28) D 
Ex-
perimen-
tal
Abbreviations D, day; N/A, not applicable
Total 
Number
1 Arm 
Duration of 
Participation
Each individual will participate in the study for approximately 11 weeks from 
the time they sign the Informed Consent Form through the final contact. After 
a screening phase of 5 weeks, each participant will receive the assigned 
intervention for approximately 4 weeks. After the end of treatment, each 
participant will be followed for an additional 2 weeks.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
There are no governance committees in this study.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 13.
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1.2
Schema
The study design is depicted in Table 1.
Table 1
Proposed Dosing Regimens of MK-1942 and Donepezil for the Study 
Treatmenta
Study Week
1
2
3
(4)
Donepezil 
(personal 
prescription)
≥10-mg, ≤15-mg QD x 28 D
MK-1942/ 
Placebo
8-mg BID x 7D
15-mg BID x 7D
30-mg BID x 7Db
≤50 -mg BID x 7Dc
(Provisional)
Abbreviations: D, day
a: There will be 18 participants randomized to receive MK-1942 and 6 participants to receive matching 
placebo. Assignment of participants to their treatments will be determined according to a computer-generated 
allocation schedule. MK-1942/matching placebo will be administered as a DFC formulation. Refer to Section 
6.6 (Dose Modification) for the safety, tolerability and PK data that will be reviewed prior to dose escalation.
b: The doses for Dose Levels 3 and 4 will be based on the safety and tolerability of the highest doses
administered in MK-1942-004 (Section 2.2.3). The dose of MK-1942 will not exceed 50-mg BID.
c: The proposed fourth dose level is provisional, pending the results of all available safety, tolerability and 
PK data from the previous dose-levels.  
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CRU = Clinical research unit, Pbo = Placebo
Figure 1
Timing of Monitoring and Interventions 
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1.3
Schedule of Activities
Study Period
Screening
Intervention (Days)a
Post-Treatment 
Safety 
Monitoring
Post-
study
Scheduled Day
Up 
to 
day  
-35
-
2
-
1
1 2
3
4
5 6 7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
42
Administrative Procedures
Informed Consent
X
Informed Consent 
for Future 
Biomedical 
Research
X
Participant 
Identification Card
X
Screening Procedures/Reviews
Medical History 
X
Prior/Concomitant 
Medication Review
X --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- X
Height (BMI)
X
Weight
X
X
X
Full physical 
examinationb
X
X
X
X
Full Neurological 
Examination
X
X
HIV, hepatitis B 
and C screen
X
Follicle Stimulating 
Hormone (FSH) 
(females only)
X
Urine Drug Screenc
X
X
CYP2C19 
Genotyping
X
MMSE-2d
X
X
X
DSSTe
X
X
X
X
X
C-SSRS 
Baseline/Screening
X
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Study Period
Screening
Intervention (Days)a
Post-Treatment 
Safety 
Monitoring
Post-
study
Scheduled Day
Up 
to 
day  
-35
-
2
-
1
1 2
3
4
5 6 7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
42
Inclusion/Exclusion 
Criteria
X
X
Domicilingf
X----------------------------------------------------------------------------------------------------------------------------------------------------------------X
Assignment of 
allocation number
X
Standard Mealsg
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Treatment Administration
MK-1942 or 
Placebo 
Administrationh
Dose Level 1
Dose Level 2
Dose Level 3
Dose Level 4 (Provisional) 
Donepezil 
Administrationi
X --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- X
Safety Monitoring
Vital Signs (heart 
rate, blood 
pressure, 
respiratory rate, 
body temperature)j, 
k
X
X X X X X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic VS 
(heart rate, blood 
pressure)j,l
X
X
X X
X
X
X
X
X
X
X
X
12-lead ECGm
X
X X X X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, 
Chemistry, 
Urinalysisn
X
X
X
X
X
X
X
X
AE/SAE Review
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Targeted 
Neurological 
Examinationo
X X
X
X X
X
X
X
X
X
X
X
X
X
C-SSRS SLAp
X
X
X
X
X
X
X
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Study Period
Screening
Intervention (Days)a
Post-Treatment 
Safety 
Monitoring
Post-
study
Scheduled Day
Up 
to 
day  
-35
-
2
-
1
1 2
3
4
5 6 7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
42
Pharmacokinetic Sampling
Blood for Plasma 
MK-1942 assayq
X X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for Plasma 
Donepezil Assayr
X X
X
X
Biomarkers
Blood for Genetic 
Analysiss
X
a If Dose Level 4 is not administered, procedures scheduled for Days 28-30 should be timed relative to the AM dose administered on Day 21.
b PE on Day 30 should be conducted ~ 48 hrs after the last dose administered on Day 28.
c May be done upon arrival in the CRU.
d Assessments on Day 28 should be given within 12 hours of the last morning dose.
e A practice assessment will be administered at screening. The assessment given on Day -1 will provide the baseline value. On Days 14 and 28, assessments should be given within 
4 hours after the AM dose. See study operation’s manual for specific instructions on test administration.
f Patients will be domiciled the entire 21-28 D of treatment, with 4 additional overnight stays (Days -2, -1, 29, 30) for pre-treatment baseline, PK assessments and for post-
treatment safety monitoring.  Patients may leave the CRU on Days 5, 6 of each dosing level at the discretion of the PI, with at-home safety and compliance monitoring.
g Patients may be provided a meal on Day 31 prior to discharge.
h Patients will take the first dose of MK-1942/placebo in the AM along with daily donepezil treatment.  Patients will be dosed BID with MK-1942/placebo, except on Day 28, 
when only the morning dose is administered.  If Dose Level 4 is not given, only the AM dose of Dose Level 3 will be given on Day 21.
i Patients will take their personal donepezil prescription QD in the AM. Those patients who do not take donepezil in the AM should be advised to start morning dosing on Day -7.
j VS measures out of normal range will be repeated up to 3 times in 15 minutes, or until measures return to normal.
k Days 1, 7, 8, 14, 15, 21, 22, and 28 are intense monitoring days: Single measures of semi-recumbent HR and BP to be taken predose (triplicate on Day 1), 2 and 4 hrs after the 
AM dose. Days -1, 2, 3, 4, 9, 10, 11, 16, 17, 18, 23, 24, and 25: Single measures of HR and BP to be taken predose and ~ 2 hrs after the AM dose. Days 29 and 30: HR and BP to 
be taken at ~ 24 and 48 hrs postdose relative to Day 28, respectively. Single measures of RR, BT taken predose on Day 1 and ~ 2 hrs after the AM dose on Days 1, 7, 8, 14, 15, 21, 
22 and 28.
l Days 1, 7, 8, 14, 15, 21, 22, and 28: Orthostatic HR and BP to be taken pre-dose on Day 1 and ~ 2 hrs after the AM dose. Days 29 and 30: orthostatic measures can be taken at ~ 
24 and 48 hrs relative to post-dose Day 28. 
m All ECGs will be measured in triplicate. Days 1, 7, 8, 14, 15, 21, 22, and 28 are intense monitoring days: predose and ~ 1, 2, 3, 4, 6, 8,and 12hours after the AM dose. Days 2, 
3, 4, 9, 10, 11, 16, 17, 18, 23, 24, and 25: predose and ~ 2 hours after the AM dose. Days 29 and 30: ~ 24 and 48 hrs after the Day 28 dose.
n Days -1, 8, 15, 22, and 28: ~ 2 hrs after the AM dose of donepezil. Day 30: ~ 48 hrs after the Day 28 dose.
o Days -1, 1: ~ 1.5 hours after AM dose of donepezil. Days 4, 7, 8, 11, 14, 15, 18, 21, 22, 25, and 28: ~ 1.5 hours after AM dose, or more frequently as required by investigator. 
Day 29: ~ 24 hrs after AM dose Day 28.
p Day 1: before AM dose. Days 8, 15, 22, and 28: ~ 4 hrs after the AM dose. Day 30: ~ 48 hrs after the AM dose on Day 28.
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Study Period
Screening
Intervention (Days)a
Post-Treatment 
Safety 
Monitoring
Post-
study
Scheduled Day
Up 
to 
day  
-35
-
2
-
1
1 2
3
4
5 6 7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
42
q Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of 
dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hr post-dose. On Days 2, 4, 8, 9, 11, 15,16, 18, 22, 23, and 25 a sample will be taken 
before the AM dose (Ctrough).  
r Days -1 and 28 are intense PK sampling days. Samples to be taken pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hrs post-dose. On Day -1 time points are relative to the morning 
donepezil dose. If Dose Level 4 is not given, Day 21 will be the second intense PK sampling day instead of Day 28. 
s Pre-dose from enrolled participants only – See Section 8.8.
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2
INTRODUCTION
 
 
 
AD is a progressive neurodegenerative disorder 
characterized by the loss of neurons from the cerebral cortex and hippocampus, and of 
cholinergic neurons in the nucleus basalis, 
 
 
 
 
 
 
 
2.1
Study Rationale
This study has the following goals: to further explore doses of MK-1942 
to evaluate 
the potential for the combinations of MK-1942 and donepezil to increase the incidence or 
severity of AEs characteristic of either agent, or the appearance of new ones; to observe any 
effects of the combination of donepezil and MK-1942 on the PK of either agent in AD 
patients. 
Regarding these interactions, previous clinical studies indicate that the primary AEs observed 
following MK-1942 administration are dizziness, headache and nausea of mild to moderate 
severity, with infrequent reports of gait abnormalities, visual disturbances, and emesis.  Some 
of these symptoms are held in common with the AE profile of donepezil, which is 
characterized by nausea, dizziness, diarrhea, emesis, muscle cramps, fatigue, bradycardia and 
syncope. Because the incidence and/or severity of these AEs may be aggravated upon co-
administration of donepezil with MK-1942, the possibility of such an interaction will be 
evaluated by administering a potentially efficacious dosing regimen of MK-1942 to a panel 
of AD patients stably maintained on donepezil (≥10-mg, ≤15-mg) as part of their treatment 
for cognitive impairment.
In addition to the potential effects of MK-1942 and donepezil co-administration, patients 
with AD frequently exhibit unsteady gait, contributing to an increased propensity for falls
[O'Keeffe, S. T., et al 1996]. The incidence of falls may be worsened by MK-1942 treatment 
at efficacious dose levels due to increased episodes of dizziness and/or gait disturbances. 
Therefore, administering MK-1942 to a population of AD patients receiving donepezil is 
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justified for determining whether an interaction of the two drugs may alter their general 
tolerability or PK.  
2.2
Background
Refer to the IB for detailed background information on MK-1942.
2.2.1
Pharmaceutical and Therapeutic Background
 
When administered to rhesus monkeys in the scopolamine-impaired object retrieval 
assessment, MK-1942 improved cognitive performance 
 
 
 
.  These effects on cognition are consistent with those observed with other, 
structurally diverse 
, both across species (mice, rats, rhesus and African 
Green monkeys) and cognitive domains (attention, working memory, episodic memory and 
executive function). 
2.2.2
Preclinical and Clinical Studies
Please refer to the Investigator’s Brochure for detailed information on the preclinical and 
clinical studies to date involving MK-1942.
2.2.3
Ongoing Clinical Studies
2.2.3.1
MK-1942-002: A Double-Blind, Placebo-Controlled, Multiple Ascending
Dose Study of the Safety, Tolerability and Pharmacokinetics of MK-1942 in 
Healthy Participants
MK-1942-002 evaluated the safety and PK of multiple oral doses of MK-1942 
 
 
 
.
Participants are being randomized to one of 6 panels, with active and placebo treatments 
being administered in a 3:1 ratio.
 
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The Cmax and AUC values achieved in this study using the DFC formulation were generally 
consistent with those reached in MK-1942-001 with the OSF at comparable dose levels. 
 
 
 
 Accumulation was consistent with the apparent terminal
hours, indicating that the PK of MK-1942 is not time dependent. 
Plasma concentrations associated with the highest dosing levels (Panels E, F) [Figure 2] were 
generally consistent with the BID dosing data from previous panels.
 
 
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Table 2
Summary of the Pharmacokinetic Parameters of MK-1942 Following Administration of Multiple Ascending Oral Doses to
Healthy Adult Subjects
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Figure 2
Mean (SD) Plasma Concentration Time Profiles for MK-1942 Following 
Administration of Multiple Oral Doses to Healthy Adult Subjects in Panels E and F (red) 
from Study MK-1942-002. (Top; Linear Scale, Bottom; Log-linear Scale)
Of the 48 total participants treated in Panels A-F, 42 reported one or more AEs. One 
participant experienced 2 episodes of moderate nausea lasting 3 hours and 15 minutes, and 2 
cases of vomiting lasting 5 and 10 minutes on days 3 and 4 of dosing. This individual 
withdrew consent for additional dosing but completed the remainder of the study monitoring 
tasks and follow-up. The second participant experienced one episode of moderate nausea 
lasting 15.5 hours accompanied by 10 minutes of vomiting on day 4 of dosing. This was 
followed on day 5 of dosing by an episode of mild nausea lasting 17.2 hours. This individual 
continued the dosing regimen and completed the study.   Otherwise, the treatment has been 
safe and generally well-tolerated, with no clinically significant, treatment-related 
abnormalities in: VS (HR, SBP, DBP, RR, BT); ECG; blood chemistry; hematology; 
neurological exams; physical exams; or behavior (suicidality). The most commonly reported 
AEs (≥2 subjects) due to all causes are: dizziness (20), headache (17), nausea (9), 
nasopharyngitis (5), diarrhea (4), sensory processing disorder (4), abdominal pain (4), 
vomiting (3), increased SBP (2), dry mouth (2) palpitations (2), abdominal discomfort (2), 
dizziness postural (2), hot flush (2), and neutropenia (2) [Table 3]. 
The incidence and severity of dizziness episodes appeared to decrease with repeated 
administration over 5-10 days at a given dose level.  
 
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 These results suggest that tolerance 
to dizziness and headache could be elicited by titrating doses of MK-1942 by BID 
administration over 7 days/dose level.
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Table 3
Subjects Reporting Adverse Events (Incidence > 0% in One or More Treatment Groups)
Screening 
Panel A 
Panel B 
Panel C 
Panel D 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Subjects in population                                            
48                             
8                             
8                             
8                             
8                             
   with one or more adverse events                          
1          
(2.1)         
5          (62.5)         
6         
(75.0)         
6          (75.0)         
5          (62.5)         
   with no adverse events                                         
47          (97.9)         
3          (37.5)         
2          (25.0)         
2          (25.0)         
3          (37.5)         
                                                                                                                                                                                                                                                                             
Blood and lymphatic system disorders              
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Eosinophilia                                                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Neutropenia                                                        
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
Cardiac disorders                                               
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Palpitations                                                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Supraventricular extrasystoles                             
0          
(0.0)         
0          
(0.0)         
0          
(0.0)        
0          
(0.0)         
0          
(0.0)         
Eye disorders                                                   
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Vision blurred                                                     
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
Gastrointestinal disorders                                   
0          
(0.0)         
2          (25.0)         
2          (25.0)         
0          
(0.0)         
3          (37.5)         
   Abdominal discomfort                                        
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Abdominal pain                                                   
0          
(0.0)         
1          (12.5)         
1          (12.5)        
0          
(0.0)         
0          
(0.0)         
   Diarrhoea                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Dry mouth                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Dyspepsia                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Nausea                                                             
0          
(0.0)         
1          (12.5)         
1          (12.5)         
0          
(0.0)         
1          (12.5)         
   Vomiting                                                           
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
General disorders and administration site 
conditions            
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
   Chest discomfort                                                 
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
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SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS)
Panel E 
Panel F 
Placebo 
Follow-Up 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Subjects in population                                               
8                                 
8                                 
8                                 
48                                 
   with one or more adverse events                                    
6           
(75.0)           
6           
(75.0)           
8           (100.0)           
1           
(2.1)           
   with no adverse events                                             
2           
(25.0)           
2           
(25.0)           
0           
(0.0)           
47           
(97.9)           
                                                                                        
                                                                                                                                                                                
Blood and lymphatic system disorders                            
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
1           
(2.1)           
   Eosinophilia                                                       
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Neutropenia                                                        
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
1           
(2.1)           
Cardiac disorders                                               
2           
(25.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Palpitations                                                       
1           
(12.5)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Supraventricular extrasystoles                                     
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Eye disorders                                                   
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Vision blurred                                                     
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Gastrointestinal disorders                                      
3           
(37.5)           
5           
(62.5)           
1           
(12.5)           
0           
(0.0)           
   Abdominal discomfort                                               
0           
(0.0)           
1           
(12.5)           
1           
(12.5)           
0           
(0.0)           
   Abdominal pain                                                     
0           
(0.0)           
2           
(25.0)           
0           
(0.0)           
0           
(0.0)          
   Diarrhoea                                                          
2           
(25.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Dry mouth                                                          
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Dyspepsia                                                          
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
   Nausea                                                             
2           
(25.0)           
4           
(50.0)           
0           
(0.0)           
0           
(0.0)           
   Vomiting                                                           
2           
(25.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
General disorders and administration site conditions    
0           
(0.0)           
2           
(25.0)           
0           
(0.0)           
0           
(0.0)           
   Chest discomfort                                                   
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
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SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS)
Screening 
Panel A 
Panel B 
Panel C 
Panel D 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
General disorders and administration site 
conditions            
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
   Chest pain                                                         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Gait disturbance                                                   
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
Infections and infestations                                   
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Nasopharyngitis                                                   
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Pharyngitis                                                        
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
Injury, poisoning and procedural 
complications                  
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Contusion                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Procedural pain                                                   
0          
(0.0)         
0          
(0.0)         
0          
(0.0)        
0          
(0.0)         
1          (12.5)         
Investigations                                                  
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Blood potassium increased                                  
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Blood pressure diastolic increased                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)        
0          
(0.0)         
0          
(0.0)         
   Blood pressure systolic increased                        
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Electrocardiogram QRS complex prolonged       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
Musculoskeletal and connective tissue 
disorders                 
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
1          (12.5)         
   Back pain                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Muscular weakness                                             
0          
(0.0)         
0          
(0.0)         
0          
(0.0)        
0          
(0.0)         
0          
(0.0)         
   Musculoskeletal stiffness                                     
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Neck pain                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
087PVJ


PRODUCT: MK-1942  
33
PROTOCOL/AMENDMENT NO.: 005-01 
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS)
Panel E 
Panel F 
Placebo 
Follow-Up 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
General disorders and administration site conditions    
0           
(0.0)           
2           
(25.0)           
0           
(0.0)           
0           
(0.0)          
   Chest pain                                                         
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Gait disturbance                                                   
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Infections and infestations                                     
1           
(12.5)           
1           
(12.5)           
3           
(37.5)           
0           
(0.0)           
   Nasopharyngitis                                                    
1           
(12.5)           
0           
(0.0)           
3           
(37.5)           
0           
(0.0)           
   Pharyngitis                                                        
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)          
Injury, poisoning and procedural complications            
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Contusion                                                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
   Procedural pain                                                    
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Investigations                                                  
1           
(12.5)           
1           
(12.5)           
1           
(12.5)           
0           
(0.0)           
   Blood potassium increased                                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Blood pressure diastolic increased                                 
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
   Blood pressure systolic increased                                  
1           
(12.5)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)          
   Electrocardiogram QRS complex prolonged                     
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
Musculoskeletal and connective tissue disorders            
0           
(0.0)           
0           
(0.0)           
2           
(25.0)           
0           
(0.0)           
   Back pain                                                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Muscular weakness                                                  
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
   Musculoskeletal stiffness                                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
   Neck pain                                                          
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
087PVJ


PRODUCT: MK-1942  
34
PROTOCOL/AMENDMENT NO.: 005-01 
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS)
Screening 
Panel A 
Panel B 
Panel C 
Panel D 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Nervous system disorders                                    
0          
(0.0)         
3          (37.5)         
5          (62.5)         
5          (62.5)         
3          (37.5)         
   Balance disorder                                                   
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Dizziness                                                          
0          
(0.0)         
3          (37.5)         
5          (62.5)         
3          (37.5)         
2          (25.0)         
   Dizziness postural                                                
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Head discomfort                                                   
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Headache                                                           
0          
(0.0)         
1          (12.5)         
2          (25.0)         
4          (50.0)         
1          (12.5)         
   Sensory disturbance                                             
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Sensory processing disorder                                
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
1          (12.5)         
0          
(0.0)         
   Somnolence                                                         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Tunnel vision                                                      
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
Psychiatric disorders                                           
0          
(0.0)         
1          (12.5)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
   Listless                                                           
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Staring                                                            
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
0          
(0.0)         
Renal and urinary disorders                              
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Leukocyturia                                                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Nocturia                                                           
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
Respiratory, thoracic and mediastinal 
disorders                 
1         
(2.1)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Nasal congestion                                                  
1          
(2.1)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
Skin and subcutaneous tissue disorders             
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
2         
(25.0)         
   Eczema                                                             
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
   Pruritus                                                           
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
087PVJ


PRODUCT: MK-1942  
35
PROTOCOL/AMENDMENT NO.: 005-01 
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS) 
Panel E 
Panel F 
Placebo 
Follow-Up 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Nervous system disorders                                        
4           
(50.0)           
6           
(75.0)           
4           
(50.0)           
0           
(0.0)           
   Balance disorder                                                   
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
   Dizziness                                                          
1           
(12.5)           
6           
(75.0)           
0           
(0.0)           
0           
(0.0)           
   Dizziness postural                                                 
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)          
   Head discomfort                                                    
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Headache                                                           
3           
(37.5)           
3           
(37.5)           
3           
(37.5)           
0           
(0.0)           
   Sensory disturbance                                                
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
   Sensory processing disorder                                        
0           
(0.0)           
2           
(25.0)           
0           
(0.0)           
0           
(0.0)           
   Somnolence                                                         
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Tunnel vision                                                      
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)          
Psychiatric disorders                                           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Listless                                                           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
   Staring                                                            
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Renal and urinary disorders                                     
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0          
(0.0)           
   Leukocyturia                                                       
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Nocturia                                                           
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
Respiratory, thoracic and mediastinal disorders            
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Nasal congestion                                                   
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
Skin and subcutaneous tissue disorders                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Eczema                                                             
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Pruritus                                                           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)          
087PVJ


PRODUCT: MK-1942  
36
PROTOCOL/AMENDMENT NO.: 005-01 
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS) 
Screening 
Panel A 
Panel B 
Panel C 
Panel D 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Vascular disorders                                              
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Haematoma                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
1          (12.5)         
0          
(0.0)         
   Hot flush                                                          
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Hypertension                                                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
   Orthostatic hypotension                                       
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
0          
(0.0)         
SUBJECTS WITH ADVERSE EVENTS 
(INCIDENCE > 0% IN ONE OR MORE TREATMENT GROUPS)
Panel E 
Panel F 
Placebo 
Follow-Up 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Vascular disorders                                              
1           
(12.5)           
1           
(12.5)           
2           
(25.0)           
0           
(0.0)          
   Haematoma                                                          
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
0           
(0.0)           
   Hot flush                                                          
1           
(12.5)           
1           
(12.5)           
0           
(0.0)           
0           
(0.0)           
   Hypertension                                                       
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)          
   Orthostatic hypotension                                            
0           
(0.0)           
0           
(0.0)           
1           
(12.5)           
0           
(0.0)           
Every subject is counted a single time for each applicable row and column.
A system organ class or specific adverse event appears on this report only if its incidence in one or more of the columns meets the incidence criterion in the report title, after 
rounding.
QD=once a day; BID=twice a day
Adverse event terms are from MedDRA Version 22.0
Source:  [P002V01MK1942: adam-adsl; adae]
CCI
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PRODUCT:  MK-1942  
37
PROTOCOL/AMENDMENT NO.:  005-01  
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
2.2.3.2
MK-1942-004: A Randomized, Double Blind, Placebo-Controlled 
Investigation of the Safety, Tolerability and Pharmacokinetics of Multiple-
Dose Regimens of MK-1942 in Healthy Elderly Participants
MK-1942-004 is a study of the safety and PK of MK-1942 when administered as multiple 
dose regimens. The study consists of 3 panels, with Panels A and C each comprised of 8 
healthy elderly participants of both genders and Panel B consisting of 8 healthy adults of 
both genders receiving either MK-1942 (N=6) or placebo (N=2). Participants will be enrolled 
in only one panel of the study. All participants are domiciled during the treatment period 
(Panel A: 21 days, Panels B and C: up to 28 days) and for 2 days after completion of dosing 
for safety monitoring (Table 5). The study will employ multiple dose and titration dosing 
regimens of varying dose levels (not to exceed 50-mg), dosing frequencies (not to exceed 
BID) and dosing durations (up to 28 days in total).
CCI
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PRODUCT:  MK-1942  
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PROTOCOL/AMENDMENT NO.:  005-01  
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
Table 5
Proposed Dosing Regimens for MK-1942-004-001
Panel
A
PK 
Break
B
PK 
Break
C
Treatment
5-mg 
BID 
x 7D
10-mg
BID x 
7 D
20-mg 
BID x 
7D
3 
weeks
8-mg 
BID 
x 7D
15-mg 
BID x 
7D
30-mg 
BID x 
7D
50-mg 
BID x 
7D
3 
weeks
8-mg 
BID 
x 7D
15-mg 
BID x 
7D
30-mg 
BID x 
7D
50-mg 
BID x 
7D
Abbreviations: BID= bis-in-diem (twice daily); D=day; PK= pharmacokinetics
As of 4 March, 2020, 8 subjects in Panel A completed the dosing regimen outlined in Table 
5.  In addition, 8 healthy adult subjects underwent treatment in Panel B.  Although data from 
both panels remains under blind, no SAEs or discontinuations were reported from panel A.  
Those AEs reported, primarily lightheadedness and headache, are reversible and of mild 
severity.  Of the 8 subjects in Panel B, 3 individuals reported multiple episodes of dizziness, 
headache and tinnitus of mild severity during treatment at dose level 2 (15 mg ID/pbo, days 
8-14 of treatment).  Two of the three individuals continued dosing at 15 mg ID/pbo for an 
additional week (days 15-21 of treatment) in lieu of escalation to dose level 3, 30 mg ID/pbo.  
After completing the second week of treatment with 15 mg ID/pbo, both participants 
withdrew themselves from the study (day 22 of treatment).  The third subject withdrew from 
the study on day 15 of treatment after having received one additional dose of 15 mg.  None 
of these 3 participants met individual stop dosing criteria for the severity of dizziness or 
nausea.  The remaining 5 participants completed all 4 dose levels up to 50 mg ID/pbo.  A 
single episode each of drowsiness and lightheadedness were reported by 2 of those subjects 
at dose level 3 (30 mg ID/pbo).  The same two subjects each reported a single episode of 
lightheadedness and headache at dose level 4 (50 mg ID/pbo).  One subject reported a brief
(5 min) episode of emesis on day 23 of treatment at dose level 4, but continued dosing at this 
level until to the end of the study.
Overall, there were no clinically significant changes in VS, ECG, targeted neurological 
exams, lab chemistry, hematology or urinalyses manifested by any participant at any point 
during the study. There were no SAEs or severe, non-serious AEs observed.  Stop dosing 
criteria were not achieved during Panels A, B.  Enrollment of Panel C is initiating using the 
dosing regimen described in Table 5.
2.2.4
Information on Other Study-related Therapy
Donepezil Hydrochloride (HCl)
Donepezil HCl is an AChEI that is marketed for symptomatic treatment of mild-to-moderate 
cognitive impairment associated with AD. The standard oral dose of donepezil HCl is one 10 
-mg tablet daily. The most common AEs associated with donepezil HCl administration 
(occurring at a frequency of ≥5% and at twice the placebo rate at the 10-mg QD dose) are 
consistent with its cholinomimetic effects and include nausea, diarrhea, insomnia, vomiting, 
muscle cramps, fatigue and anorexia. These AEs are mild in intensity and transient, typically 
resolving with continued donepezil HCl treatment without the need for dose adjustment 
[Jackson, S., et al 2004]. Less commonly observed AEs include depression and sleep 
disturbances (eg, abnormal dreams and somnolence).
087PVJ


PRODUCT:  MK-1942  
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PROTOCOL/AMENDMENT NO.:  005-01  
MK-1942-005-01 FINAL PROTOCOL
16-MAR-2020
Donepezil HCl is ~96% bound to human plasma proteins over the concentration range of 2 to 
1000 ng/mL. It is extensively metabolized by the CYP 450 isoenzymes 2D6 and 3A4, 
undergoes glucuronidation, and is excreted in the urine as the parent compound, four major 
metabolites (two of which are known to be active), and several incompletely identified, 
minor metabolites. Donepezil HCl has a Tmax of ~3 to 4 hours and half-life ~70 hours.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical trials will directly benefit from treatment 
during participation as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Details of the hypotheses to be tested can be found in Section 9.3.
Objectives
Endpoints
Primary
•
Evaluate the safety and tolerability of 
treatment (MK-1942 co-administered
with donepezil) in AD patients with mild-
to-moderate cognitive impairment.
•
Safety measures (VS, ECGs, clinical 
chemistry, hematology, urinalysis, 
targeted neurological exams, Columbia 
suicide severity rating scale) and 
Adverse Event reports
Secondary
•
Evaluate the effects of donepezil on the 
PK of MK-1942 in AD patients
Hypothesis
o
The plasma Cmax of MK-1942 
determined on the last day of a 
titrated treatment regimen (Day 21 
[28]) when co-administered with 
donepezil to AD patients is similar 
to the Cmax obtained following 
administration of MK-1942 to 
HEV from MK-1942-004, Panel 
C. That is, the true GMR (MK-
1942 + donepezil in AD / MK-
1942 in HEV) is contained within
the interval (0.5, 2.0).
•
Cmax, AUC0-12, AUC0-24, Ctrough, 
Tmax, apparent terminal t1/2, CLss/F, 
and Vzss/F of MK-1942
•
AUC0-24, Cmax, Ctrough, Tmax for 
donepezil
087PVJ


PRODUCT:  MK-1942  
40
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Objectives
Endpoints
•
Evaluate the effects of MK-1942 on the 
PK of donepezil in AD patients. 
Estimation: 
o
The true GMRs of plasma PK 
parameters (AUC0-24, Cmax) for 
donepezil before and during 
administration of donepezil + 
MK-1942 to AD patients will be 
estimated.
Tertiary/Exploratory
•
Evaluate the changes in cognitive 
function of AD patients by comparing the 
MMSE-2 and DSST scores obtained at 
baseline with those from the last day of 
dosing. 
•
Explore the relationship between plasma 
concentrations of MK-1942 and corrected 
QT intervals.
•
•
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.
•
MMSE-2 scores 
•
DSST scores
•
QTcF

Germline genetic variation
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, multi-site, double-blinded study of the safety, 
tolerability and PK of MK-1942 when co-administered with donepezil.  Specifically, the 
study will evaluate the safety and PK of a selected MK-1942 titration dosing regimen 
administered to AD patients with mild cognitive impairment currently being treated with a 
stable dose of donepezil (≥10-mg, ≤15-mg QD).  
Participants will be domiciled starting 2 days before treatment, during the MK-1942 
treatment period (up to 28 days) and for 3 days after completion of dosing for safety 
monitoring and PK sampling (Table 1, see Section 1.3, SoA). Participants may elect to spend 
days 5 and 6 of each dose level at home with concurrence of the PI.  Safety and PK 
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monitoring will be conducted throughout the domiciled treatment period and post-treatment 
follow-up, with safety ensured by monitoring AEs, VS, 12-lead ECGs, as well as conducting 
lab safety tests, neurological examinations, PE, and administering the C-SSRS at the times 
indicated (see Section 1.3).  The precise timing of ECGs, blood sampling for PK, clinical and 
hematology labs and/or other procedures listed in Section 1.3 may be altered at any time 
during the study based on newly available data.  Participants who elect to spend time at home 
will be monitored at home by telephone to record AE episodes and treatment compliance.
The study will employ titration dosing regimens of varying dose levels (not to exceed 50-
mg), dosing frequencies (not to exceed BID) and dosing durations (up to 28 days in total) 
(Table 1, Figure 1). The decision to titrate doses upwards within a panel and to proceed to 
subsequent panels will be made by the investigator with mutual agreement from the Sponsor 
based on all available safety and PK information from previous dose levels.
The doses of MK-1942 proposed for administration may be adjusted in terms of dose level, 
dosing frequency or duration, within the limits described above. Details of the decision-
making process informing dose escalation are provided in Section 6.6.
Because this is a Phase 1 assessment of MK-1942 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The objectives of this study include determining if the combination of MK-1942 with 
donepezil increases the incidence or severity of AEs previously reported for these agents, or 
results in unanticipated AEs in the patient population targeted for MK-1942 treatment.  In 
addition, any changes in the PK parameters of either MK-1942 or donepezil as a result of co-
administration will be assessed.
The study will investigate the effects on safety and PK of co-administration of MK-1942 to 
AD patients with mild-to-moderate cognitive impairment who are under stable treatment 
with a treatment regimen of donepezil (≥10-mg, ≤15-mg).
 
 
 
 
 
  Participants will be domiciled for the 
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duration of treatment with the combination of donepezil and MK-1942/placebo in order to 
ensure adequate safety monitoring and treatment compliance.
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The safety and tolerability of MK-1942 when administered in the multiple dose regimens 
proposed will be monitored throughout the study by collecting the following safety 
endpoints: direct assessment/reporting of AEs; physical and neurological exams; C-SSRS 
endpoints; semi-recumbent and orthostatic VS measures (SBP, DBP, HR, RR, BT); 12-lead 
ECG parameters; and laboratory safety tests (serum chemistry, hematology, and urinalysis). 
Clinically meaningful changes in VS and ECGs were not observed in studies MK-1942-001, 
MK-1942-002 and MK-1942-003 (See MK-1942 IB). However, dizziness, headache, nausea 
and emesis of mild to moderate severity lasting <24 hours were observed following MK-
1942 administration and will be monitored using AE reports, direct observation and targeted 
neurological exams, including gait assessments taken ~2 hours post-dosing. Monitoring the 
incidence and severity of episodes of dizziness and the application of stopping criteria, as 
well as evidence for the development of tolerance to the induction of dizziness by MK-1942,
will form the basis for careful escalation between dose levels, thereby minimizing the safety 
risks for subjects participating in this study. The stopping rules, based on observations of 
dizziness, nausea and emesis (Section 7.1.1), will be applied to the group on a per-panel and 
individual within-panel basis.
ECG and VS monitoring will be scheduled in proximity to the Cmax 
 
 after each dose and for up to 2 weeks after the last dose. Prior to 
starting treatment on Day 1, baseline VS parameters will be recorded in triplicate (Section 
8.0) and the average of each parameter will serve as a baseline for comparison to 
subsequently recorded VS parameters. The relationship between the plasma concentration of 
MK-1942 and ECG parameters (including QTc) will be assessed as an exploratory objective.
The C-SSRS prospective assessment of suicidal ideation and behavior will be included in this 
study in compliance with the 2012 FDA guidance requiring prospective assessment in 
clinical trials conducted under IND applications and trials that are intended for submission in 
a NDA to the Neurology or Psychiatry Divisions of the FDA or biologics license application, 
as well as assessment in trials 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). The 
Baseline/Screening version of the C-SSRS will be administered at screening, while the Since 
Last Assessment version of the C-SSRS/SLA will be given at several points during and after 
treatment administration to all subjects enrolled, including at the Post-trial visit (see Section
8.0).
In addition to regular safety monitoring conducted during the treatment period, subjects will 
remain in the clinic for three additional days of post-dose safety monitoring and PK sampling 
at the end of the treatment period (Section 8.0). This post-treatment period allows for plasma
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MK-1942 levels to decline so that any changes in C-SSRS endpoints resulting from a 
decrease in exposure may be manifested.  
Additional details on the safety and toxicology of MK-1942 as determined in preclinical 
investigations are provided in the MK-1942 IB. In summary, CV and respiratory safety 
studies in monkeys, rats and guinea pigs noted no significant changes in VS or ECG 
parameters following exposures to MK-1942 in excess of those anticipated following 
projected efficacious doses.
In summary, preclinical toxicology as well as clinical safety findings for MK-1942 suggest 
that it will be safe,
 
at steady state for the highest dose proposed in this investigation (50-
mg BID). Nonetheless, the incidence and severity of AEs observed following direct reports 
and targeted neurological exams will be recorded at multiple timepoints during the study to 
aid in dose escalation decisions.
Pharmacokinetic Endpoints
The plasma PK of MK-1942 following multiple dose co-administration with donepezil will 
be characterized by determining the Cmax, Tmax, Ctrough, and AUC0-12 after the first dose. 
In addition, Cmax, Tmax, Ctrough, AUC0-12, AUC0-24, apparent terminal t1/2, CLss/F, 
Vzss/F and accumulation ratio will be determined at steady state.  This will allow doses and 
dosing regimens in elderly participants with AD to be identified that produce systemic 
exposures in the predicted efficacious range 
 
 while providing insights into the ability of donepezil to alter the PK of MK-
1942.
Similarly, the plasma PK of donepezil following once daily administration will be 
characterized by determining the Cmax, Tmax, and AUC0-24 on the day before 
administration of the first dose of MK-1942 and after 21 (28) days of co-administration.  
Determining the Cmax and AUC0-24 of donepezil during co-administration with MK-1942 
will provide insights into the ability of MK-1942 to alter the PK of donepezil.
Exploratory Endpoints
The Mini-Mental State Exam, edition 2 (MMSE-2) will be administered to AD patients at 
screening and upon completion of up to 28 days of treatment.  The score from the MMSE-2 
given at screening will be used as an inclusion criterion, to ensure that AD patients being 
enrolled fall into the cognitive impairment categories of mild to moderate severity.  The 
MMSE-2 is a 30-point examination evaluating Registration, Orientation to Time, Orientation 
to Place, Attention, Recall, Language, Repetition, Complex Commands, and Recall tasks.  A 
score between 21 to 26 typically indicates that a subject is experiencing mild cognitive 
impairment, while scores in the range of 10-20 are indicative of patients with moderate 
cognitive impairment.  This study proposes to enroll individuals with mild to moderate 
cognitive impairment as indicated by scores between 17 to 26.  This range will allow for 
broader recruitment while reducing the burden on CRU personnel associated with caring for 
patients with MMSE-2 scores < 17.  In addition to its use as a screening tool for identifying 
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candidate participants as having mild to moderate cognitive impairment, the MMSE-2 will be 
used as an exploratory endpoint to determine whether the treatment regimen results in any 
changes from the initial score.
The WAIS-R Digit Symbol Substitution Test (DSST) is a test of processing speed and 
working memory.  The DSST will be used in this study as an exploratory endpoint for
rapidly assessing whether treatment enhances cognition, as well as a safety signal for the 
development of treatment-induced cognitive decline. DSST scores from tests administered at
the middle and the end of the study will be compared to the baseline score to determine if 
treatment has any effect on cognitive function.  
4.2.1.2
Planned Exploratory Biomarker Research
4.2.1.2.1
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 absorption, distribution, metabolism, and excretion; 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.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebo will be used in this trial to allow for an appropriate assessment of the safety data of 
MK-1942, any impact of MK-1942 treatment on donepezil PK, and to maintain study 
blinding to reduce bias.
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 biologics license application, 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
The rationales for the doses and estimated exposures are detailed in Sections 4.3.1 and 4.3.2.
As this is a Phase 1 assessment of MK-1942 in humans, and the PK, PD 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 8.11.6.
4.3.1
Starting Dose for This Study
The study starts by administering 8-mg MK-1942/placebo BID for 7 days. Thisdose level 
was well-tolerated in study MK-1942-002, 
, similar to those observed after a single 12-mg dose. 
When this dose level followed administration of 5-mg BID x 7D in Panel D of PN002, it was 
associated with 4 episodes of the non-serious AEs of dizziness and headache/head discomfort
of mild severity, resolving in <6 hours. Because the AEs observed with the 8-mg BID dose 
were mild and reversible and the frequency and severity of these episodes declines with 
repeated dosing over 7 days, this dose level is considered a suitable start for the titration 
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dosing regimen proposed for this investigation, where each dose level increases in increments 
of approximately 2-fold.
4.3.2
Maximum Dose/Exposure for This Study
Preclinical investigations with an 
 analog of MK-1942 indicate that the 
cognitive performance of scopolamine-impaired NHP in the object retrieval assay are 
maximized following a repeat dosing regimen that achieves steady-state plasma 
concentrations
 
  Given that the equivalent doses may be required for clinically significant 
levels of efficacy, an objective of this study is to determine the safety and tolerability of 
donepezil/MK-1942 co-administration using doses of MK-1942 
 
 (Table 6).  The exploration of doses of MK-1942 
 
 is supported by the relative safety and tolerability of doses of 20-mg 
 
 when administered in previous investigations using a titration dosing 
regimen (see Section 2.2.3.1.).
Figure 3
Amelioration of Scopolamine-Induced Cognitive Impairment 
 
Table 6
Projected Systemic Exposures and Receptor Occupancies Achieved at Steady 
State with the Proposed Dose Levels. 
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Because the PK parameters of MK-1942 increase linearly in a dose-dependent fashion, data 
from protocol MK-1942-002 (Table 2, Section 2.2.3) was used to project the steady-state 
exposures obtained following administration of higher doses of MK-1942 than previously 
administered, assuming that MK-1942 PK is similar in elderly and non-elderly subjects.  
 
 
 
 
  
 
 
 
 
 
 
. Moreover, the 50-mg dose will only be administered if the 30-mg BID x 7D 
dose level is found to be safe and well tolerated, as defined by the stop dosing criteria (see 
Section 6.6.1). Finally, if the 50-mg dose is not tolerated by participants in MK-1942-004, 
Panels B and C, this dose will not be administered in the provisional dose level period.
4.3.3
Rationale for Dose Interval and Study Design
MK-1942 is being developed as an adjunct to current therapies (eg, AChEI) for the treatment 
of cognitive impairment associated with Alzheimer’s dementia.  The intent of this 
investigation is to evaluate the safety, tolerability and PK of MK-1942 when combined with 
the most commonly prescribed AChEI, donepezil in AD patients.  Doses of donepezil
appropriate for treating cognitive impairment associated with AD will be co-administered 
with a dosing regimen of MK-1942 projected to achieve potentially efficacious receptor 
occupancies 
.  These RO values are based 
on observations of the ability of MK-1942 
 to reverse cognitive 
impairment in preclinical models (object retrieval performance in scopolamine-impaired 
NHP).  The proposed regimen will also help to establish MK-1942 dosing margins for a safe 
treatment regimen. 
Clinical investigation MK-1942-002 (Section 2.3.3) indicated that administration of 
MK-1942 BID over at least 7 days was associated with a decrease in the incidence of 
episodes of dizziness, headache and other AEs. This tolerance to the adverse effects of 
MK-1942 was typically manifested after at least 5 days of dosing. 
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In summary, this study proposes the co-administration of MK-1942 with donepezil, using a 
titration dosing regimen of MK-1942 BID for 7 days per dose level, with a maximum dose 
level of 50-mg
 
  
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
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.
An objective of this early Phase 1 study is to identify a safe and well-tolerated dosing 
regimen that achieves the PK, PD, and/or biologic targets in humans based on preclinical or 
early clinical data. Therefore, it is possible that study participants may not receive all doses 
specified in the protocol if this objective is achieved at lesser dose levels. This would not be 
defined as early termination of the study, but rather an earlier than anticipated achievement 
of the study objective(s). If a finding (eg, PK, pharmacodynamic, safety, etc.) from another 
preclinical or clinical study using the study intervention(s), comparator(s), drug(s) of the 
same class, or methodology(ies) used in this study results in the study(s) or program being 
stopped for non-safety reasons, this also does not meet the definition of early study 
termination.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical 
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
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5
STUDY POPULATION
Men and WONCBP with mild-to-moderate cognitive impairment associated with AD and
between the ages of 50-85 (inclusive) will be enrolled this study. The degree of cognitive 
impairment in these candidates will be determined based on their MMSE-2 score (17-26) 
taken at screening. There should be no more than ~17 (~70%) patients with MMSE-2 scores 
consistent with mild cognitive impairment (21-26) enrolled in the trial.  Similarly, there 
should be no less than ~7 (~30%) patients with MMSE-2 scores consistent with moderate 
cognitive impairment (17-20) enrolled in the trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Have a BMI > 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.
2. Is in good health based on medical history, physical examination, VS measures and 
ECG performed prior to randomization. 

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 two months 
and who are not receiving any proscribed medications for treatment may be 
enrolled if clinically acceptable to the investigator and Sponsor. 
Section 10.8, Appendix 8 provides a table of 12-Lead ECG Abnormality Criteria.
3. Is in good health based on laboratory safety tests obtained at the screening visit. 
Appendix 10.2 provides a table of laboratory safety tests to be performed. Appendix 
10.10 provides an algorithm for the assessment of out of range laboratory values.
4. Have a negative UDS prior to randomization.
5. Report a history of cognitive and functional decline with gradual onset and slow 
progression for at least one year before Screening, that is either corroborated by an 
informant who knows the subject well or is documented in medical records.
6. Have a MMSE-2 score ≥17 to ≤26 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.
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7. Be receiving donepezil (maximum dose: ≥10-mg, ≤15-mg) for symptomatic treatment of 
cognitive impairment associated with Alzheimer’s dementia. The dose level must be 
stable for at least 1 month prior to screening. 
8. Have a reliable and competent trial partner/caregiver who has a close relationship with 
the subject, has face-to-face contact at least three days a week for a minimum of six 
waking hours a week, and is willing to accompany the participant, if desired, to trial 
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 trial 
partner/caregiver should understand the nature of the trial and adhere to trial requirements 
(eg, dosing, visit schedules, and nature and number of evaluations).
Demographics
9. Is male or female, from 50 years to 85 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
10. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least an additional 90 days (a spermatogenesis cycle) after 
the last dose of study intervention:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
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Female Participants
11.
A female participant is eligible to participate if: 
-
She is a WONCBP, as defined in Appendix [5].
Informed Consent
12.
The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study 
without participating in future biomedical research.
Additional Categories
13.
Is willing to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
2. Is at imminent risk of self-harm, based on clinical interview and responses on the C-
SSRS, or of harm to others in the opinion of the investigator. Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method
(eg, positive response to item 4 or 5 in the assessment of suicidal ideation on the C-
SSRS) in the past 5 years or suicidal behavior in their lifetime.
3. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit.
4. Has a 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.
5. Candidates should not have a history of asthma, COPD, urinary obstructions or GI 
bleeding.
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6. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated non-melanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
7. Participant has an estimated eGFR ≤60 mL/min/1.73 m2 based on the MDRD.
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creat)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if African American])
At the discretion of the investigator a measured creatinine clearance, 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 creatinine clearance of up to 10% below of 
either 80 mL/min (for creatinine clearance) or 80 mL/min/1.73m2 (for eGFR) may be 
enrolled in the study at the discretion of the investigator.
8. Has a 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 non-prescription drugs or food.
9. 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.
Prior/Concomitant Therapy
10. All medications being taken by candidates for enrollment in the study should be 
reviewed by the PI and the Sponsor to determine their propensity for altering MK-1942 
exposure, or for MK-1942 to interfere with the metabolism of the medication. 
Medications prescribed for the candidate that are stably treating a condition should not 
be interrupted. Candidates should not be enrolled if they are taking
 
 
Enrollment of candidates taking prescription 
drugs that can alter QTi for an underlying condition (including: anti-arrhythmics 
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[quinidine, procainamide, disopromide, dofetilide, sotalol], some antihistamines, 
antidepressants [tricyclics, doxepin, fluoxetine] and antimicrobials) should be avoided. 
See Section 8.1.5 for more examples of excluded agents.
Prior/Concurrent Clinical Study Experience
11. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
13. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females).
Other Exclusions
14. Is under the age of legal consent.
15. 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 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
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. 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 UDS prior to 
randomization.
19. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
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.
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, including but not limited to laboratory safety 
evaluations, are specified below.
Participants will fast for at least 8 hours prior to laboratory safety evaluations.
On all dosing days, participants will fast from all food and drinks, except water, for at least 8 
hours prior to study drug administration in the morning and for 2 hours post-dose following 
the morning and evening dose. After the 2-hour post-dose procedures have been completed, 
subsequent meals and snacks will be unrestricted in caloric content, composition and timing, 
except for dinner. Dinner must be consumed at least 2 hours prior to administration of the 
second dose of study treatment. Participants will fast from all food and drinks except water 
between meals and snacks. The caloric content and composition of meals will be the same on 
each day in each panel.
Water will be provided during study drug administration, with the restrictions noted above. 
Water will be restricted 1 hour prior to and 1 hour after study drug administration.
Each study drug administration will need to be taken with at least 240 mL (not to exceed 500 
mL) of water.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study including the washout interval between treatment periods and 
until the post-study visit.
On full PK sampling days, participants will refrain from the consumption of all fruit juices 8 
hours prior to study drug administration and 2 hours following the morning and evening 
dose.
On intermediate days and all other days during the study, the consumption of all fruits and 
fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 8 hours prior to the pre-study and post-study visits. On full PK sampling days 
participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 8 hours prior to study drug administration in the morning, and for 2 hours 
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following the morning and evening dose. At all other times, caffeinated beverages or 
xanthine-containing products will be limited to no more than 6 units per day amounts (>6 
units: 1 unit = 120-mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the pre-study and 
post-study visits and while domiciled on the CRU.
At all other times during the study (screening to post-study visit), alcohol consumption is 
limited to no more than approximately 3 alcoholic beverages or equivalent (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce]) per day.
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, weight lifting, running, 
bicycling, etc.) from the pre-study (screening) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention OR withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s 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 prior to dosing the replacement supplies. 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 7.
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Table 7
Study Interventions
Arm 
Name
Arm 
Type
Interven-
tion Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen
Use
IMP/
NIMP
Sourcing
AD 
Patients
Experi-
mental
MK-1942
Drug
Capsule
1-mg
5-mg
10-mg
All 
dosage 
levels *
Oral
BID 
dosing 
for up to 
28 days
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
AD 
Patients
Experi-
mental
Donepezil
Drug 
Tablet
5-mg
10-mg
All 
dosage 
levels
Oral
QD 
dosing 
for up to 
28 days
Thera-
peutic
NIMP
Provided by 
participant
AD 
Patients
Placebo
Placebo to 
MK-1942
Placebo
Capsule
N/A
All 
dosage 
levels
Oral
BID 
dosing 
for up to 
28 days
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
* Doses of MK-1942 may be adjusted based on available safety/PK data from previous panels. The required dose will be achieved by administering multiples of 
the available capsule strength.
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All supplies indicated in Table 7 will be provided per the "Sourcing" column depending upon 
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.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided inSection 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.
087PVJ


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39-


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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 prior to 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.
 
 
 
 
 
. Any prescribed medications used to stably treat a screening candidate or 
enrollee should be evaluated by the investigator in cooperation with the Sponsor to determine 
its propensity to interact with MK-1942 in any way before altering the treatment or enrolling 
the candidate. A more complete list of concomitant medications that should be avoided 
include:
1.
Drugs that can alter QTi for an underlying condition (including: anti-arrhythmics 
[quinidine, procainamide, disopromide, dofetilide, sotalol], some antihistamines, 
and antimicrobials) should be avoided.
2.
All AChEI’s other than donepezil (physostigmine, neostigmine, echothiophate, 
pyridostigmine, rivastigmine, galantamine, tacrine, edrophonium, 
succinylcholine, etc.).
3.
All medications with anticholinergic effects (atropine, darifenacin, dicyclomine, 
diphenoxylate with atropine, hydroxyzine, fesoterodine, glycopyrrolate, 
hydroxyzine, hyoscyamine, ipratropium, oxybutynin, promethazine, tolterodine, 
trospium, promethazine).
4.
Sedatives/benzodiazepines (eg, alprazolam, diazepam). Use of some non-
benzodiazepine medications for sleep may be acceptable if stable for at least two 
months before the Screening Visit, following review by the Investigator and 
Sponsor.
5.
Narcotic analgesics (eg, codeine, morphine, hydromorphone, oxycodone).
6.
Thyroid hormone replacement.
7.
8.
Any herbal/natural product containing St John’s wort, valerian, cassia, or licorice 
(glycyrrhizin) are restricted from use.
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Paracetamol/acetaminophen may be used for minor ailments without prior 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/Titration/Other)
6.6.1
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
Overall dose escalation will be limited by achievement of NOAEL exposure limits, loss of 
participants due to intolerance, or completion of the scheduled dose escalation.
Discontinuation of an individual participant from the study will be considered in the event of:
clinically significant abnormalities in any safety tests as confirmed by the investigator; or any 
medical or non-medical circumstances which, in the opinion of the investigator, pose a risk to 
the patient by continuing in the study, or which do not allow the patient to adhere to protocol 
requirements. The Sponsor medical monitor should be notified within approximately 24 
hours when either of these circumstances occurs.
The stopping rule listed below will be employed during the conduct of this study. If this
criterion is met, the study may be paused until the Sponsor has reviewed the totality of data 
available. 
a.
An individual participant reports a Serious Adverse Event considered related to the 
study drug by the investigator. Two (2) or more participants within a Part (at the same 
dose level) report Severe Non-serious Adverse Events considered related to the study 
drug by the investigator.
If any of these criteria are met, subsequent doses of treatment for remaining participants may 
be adjusted (maintained at the same level, decreased or halted) based upon joint agreement of 
the Sponsor and investigator.
6.6.2
Dizziness/Nausea Stopping Criteria
Dizziness
Previous investigations (MK-1942-001, 002, 003) reported increases in the incidence and 
severity of dizziness episodes with doses of MK-1942 ≥8-mg. These results suggest that the 
AE of dizziness may occur over the dose range proposed for this study and that the number 
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and severity of dizziness episodes should be monitored as part of the dose escalation stopping 
criteria.  
The following parameters are used for determining whether to adjust dosing for an individual 
based on the presence of dizziness:
A sustained symptom, defined as lasting ≥ 4 hours in duration and;
A severity of Grade 2 (“Moderate”) intensity of dizziness, defined as including:

Subject reports feeling a spinning or swaying movement that is not relieved 
when supine; AND

Subject reports feeling unsteady or about to lose their balance upon walking
(postural dizziness); AND/OR

The Targeted Neurological Examination records that gait or extraocular 
movements are impaired.
If a participant reports sustained dizziness that, in the opinion of the investigator, is of 
moderate or greater severity and is related to study drug administration, then the dose for that 
participant will not be escalated. Continued dosing of the individual at the same or a lower 
level may be considered, or dosing may be stopped.
Nausea
Episodes of nausea were reported during studies MK-1942-001 (see MK-1942 IB) and MK-
1942-002 [Sec. 2.2.3]. These events were observed less frequently than those of dizziness 
and were mild to moderate in intensity. The results suggest that the AE of nausea may occur 
over the dose range proposed for this study and that the number of episodes and theirseverity 
should be monitored as part of the dose escalation stopping criteria.
The definition of Grade 2 (“Moderate”) severity nausea includes signs and symptoms that 
interfere with activities of daily living but require no treatment or intervention. If participants 
show sustained (> 4 hrs) physical signs and/or symptoms of nausea that, in the opinion of the 
investigator, are of moderate or greater severity and are related to study drug administration, 
then the dose for that participant will not be escalated. Continued dosing at the same or a 
lower level may be considered, or dosing for that individual may stop. If considered 
necessary by the investigator, supportive care may be provided until the signs/symptoms 
return to baseline.
Stopping Criteria
If >2 subjects meet the criteria defined above, there will be no dose escalation. 
Administration of study treatment to all participants may continue at the same or lower dose, 
for a longer duration of administration (not to exceed the 28-day limit), or may be halted, 
with agreement of the investigator and Sponsor. 
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These rules are not meant to be comprehensive but to provide clear guidance for the 
adjustment or discontinuation of dosing. However, due to the uncertain nature of Phase 1 
trials, these rules should not be considered a substitute for clinical judgment. If unforeseen 
events demonstrate that participants meet these stopping criteria, but clinical judgment allows 
for continuance, then with the agreement of the Investigator and the Sponsor, and with the 
consent of the participant, dosing may be continued. Conversely, if the participant does not 
meet the criteria warranted by the stopping rules but clinical judgment mandates that dosing 
be halted, then dosing of the participants may be discontinued.
Participant 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 future biomedical research, 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., 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.
6.7
Intervention After the End of the Study
There is no study-specified intervention following 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.
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.
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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 prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in 
Section 1.3 and Section 8.1.9, or if available, a protocol clarification letter.
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 Sections 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 2 consecutive 
days or has 2 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 UDS at any time during the course of the study.
For participants 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.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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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 future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
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•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
Procedures conducted as part of a site generic screening (with an ERC/IRB approved site 
generic screening consent) on potential participants (eg, blood count, vital signs, ECG, 
etc.) and obtained before signing of study ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol specified criteria and were performed 
within the screening window defined in this protocol.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 500 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research.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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
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A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the future biomedical research consent to 
the participant, answer all his/her questions, and obtain written informed consent before 
performing any procedure related to future biomedical research. A copy of the informed 
consent will be given to the participant.
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 
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the participant provides written informed consent. At the time of intervention randomization,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history 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 prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 4 weeks or 5 half-lives before the screening visit. Any medications necessary for 
keeping a candidate stably treated for an underlying condition should be reviewed by the PI 
for potential interference with/by the study medication
 and brought 
to the attention of the Sponsor for mutual agreement on whether to enroll the candidate in the 
study (Section 6.5).  Participants will be stably maintained on donepezil (≥10-mg, ≤15-mg) 
for at least 1 month prior to enrollment.
8.1.5.2
Concomitant Medications
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, ≤15-mg) for 
at least 1 month prior to enrollment.
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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive an allocation number. 
The allocation number identifies the participant for all procedures occurring after treatment 
allocation. Once an allocation number is assigned to a participant, it can never be re-assigned 
to another participant.
A single participant cannot be assigned more than 1 allocation number.
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8.1.8
Study Intervention Administration
Study intervention should begin on the day of treatment allocation/randomization or as close 
as possible to the date on which the participant is allocated/assigned. All doses of study 
treatment (MK-1942/placebo) will be provided as dry filled capsule and matching placebo.
These will be administered orally with at least 240 mL (not to exceed 500 mL) of water upon 
completion of all pre-dose procedures for that day, with administration of study medication 
witnessed by the investigator and/or study staff. Subjects will not be allowed access to food 
for 2 hours after both the morning and evening doses.
8.1.8.1
Timing of Dose Administration
The first oral doses of MK-1942/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-1942 or placebo will be administered (Section 8.1.8), with the 
time of administration constituting Time “0”. All capsules will be distributed and consumed 
within 10 minutes of the recorded administration time. Participants will remain resting in bed 
in a semi-recumbent position for approximately 2 hours after dosing. Participants may 
ambulate freely after the 2-hour VS and ECGs if no clinically significant changes are
observed.
Participants will receive the second daily oral dose of MK-1942/placebo approximately 12 
hours after the time the first daily dose was administered. All capsules will be administered 
within 10 minutes of the of the exact time when treatment is administered, and that 
administration time recorded. On Day 21 (28), only the morning dose will be administered. 
Participants will remain resting in bed in a semi-recumbent position for approximately 2 
hours after dosing. Participants may ambulate freely after the 2-hour VS and ECG measures 
if no clinically significant changes are observed.
Donepezil will be administered in the mornings at approximately the same time as 
MK-1942/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. 
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. If a participant discontinues for any reason at any 
time during the course of the study, 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.
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8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to 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 
grade of the AEs observed, the relation to study drug, the reason thereof, etc., in the medical 
chart. If it is not possible to record this assessment in the chart prior to 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 principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
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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
Participants will report to the clinical research unit (CRU) on Day -2 prior to the scheduled 
day of administration of the study treatment or at the discretion of the investigator.
Participants may be domiciled in the unit for -2 days before dosing study drug, for up to 28 
days of treatment, and with an additional three days of in-house, post-treatment follow up. 
Participants will be released from the CRU with instructions to return for the post-study 
examination, to be performed 14 days after the last day of dosing.
At the discretion of the investigator, participants may request to go home for days 5 and 6 of 
each dose level.  At-home monitoring of AEs and treatment compliance will be conducted by 
daily telephone calls from the CRU.  Participants should return to the CRU the evening of 
day 6 of each dose level in order to be ready for procedures conducted the following 
morning.
At the discretion of the investigator, participants may be requested to remain overnight in the 
CRU for longer than 30 days. 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 on how to continue monitoring the participant will 
be at the discretion of the investigator after discussion with the Sponsor.
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/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from pre-study 
to post-study visits), including approximate blood volumes drawn by visit and by sample 
type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI)
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1-0.4 round down and 0.5-0.9 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, pulse rate, respiratory rate, and blood 
pressure will be assessed.
•
Blood pressure 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.
•
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest 
by 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 semi-recumbent position for at least 10 minutes prior to 
having VS measurements obtained. Semi-recumbent VS will include HR and BP. The correct 
size of the BP cuff and the correct positioning on the participants' arm is essential to increase 
the accuracy of BP measurements.
The pre-dose (baseline) HR and BP will be triplicate measurements, obtained at least 1-2 
minutes apart within 3 hours before dosing MK-1942 on Day 1. The mean of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). On all other days indicated in the SoA (See Section 
1.3) pre-dose HR and BP will be single measurements. Post-dose VS measurements will be 
single measurements unless there is an out-of-range reading. In this case, at least three 
measures of VS (either resting or orthostatic HR, BP) will be taken within a 15-minute 
period, or until readings fall into normal range.
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Participants will continue to rest semi-recumbent from dosing until 2 hours post-dose, except 
to stand for the measurement of orthostatic VS or other study-related procedures.
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 BP) will be obtained. Participants should be semi-recumbent for at 
least 10 minutes and then stand upright for 2 minutes prior to measurement of orthostatic VS.
8.3.3
Electrocardiograms
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent for at least 10 minutes prior to each 
ECG measurement.
The correction formula to be used for QTc is Fridericia.
As repeat ECGs are required in this study, 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.
All ECGs will be taken in triplicate at least 1-2 minutes apart at the times/dates indicated in 
the SoA (See Section 1.3). The mean of these measurements will be used to calculate the 
change from baseline for safety evaluations and for rechecks, if needed. Pre-dose ECGs will 
be obtained within 3 hours before dosing MK-1942/placebo.
During each treatment period, if a participant demonstrates an increase in mean QTc interval
≥ 60 msec compared to the mean pre-dose baseline measurement, the participant will be 
monitored by recording 12-lead ECGs in triplicate every 15 minutes for at least 1 hour, or 
until the QTc is within 60 msec of baseline. If prolongation of the QTc interval ≥60 msec 
persists, a consultation with a study cardiologist may be appropriate and the Sponsor should 
be notified.
If the QTc interval is 500 msec, the Sponsor should be notified, and the ECGs should be 
reviewed by a cardiologist. The ECG reader will be blinded to treatment, treatment period 
and timepoint. The participant may be telemetry-monitored until the QTc is < 500 msec or 
should be considered for transfer to a location where closer monitoring and definitive care 
(eg, a cardiac or intensive care unit) is available.
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If the participant has unstable hemodynamics or if any clinically significant dysrhythmias are 
noted, the participant should be immediately transferred to an acute care setting for definitive 
therapy.
A study cardiologist will be consulted by the PI as needed to review ECG tracings with 
abnormalities.
8.3.4
Neurological Exams
The full neurological exam monitors aspects of mental status, cranial nerve function, motor 
system function, reflexes, coordination and gait and sensory function (Appendix 11) and will 
be administered at screening and the post-trial exam. The targeted neurological exam 
contains Modules 1, 2 and 5 of the general examination, focusing on arousal, cranial nerve 
function, and gait.
8.3.5
Mini-Mental State Examination (MMSE-2)
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. 
8.3.6
WAIS-R Digit Symbol Substitution Test (DSST)
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. 
8.3.7
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.8
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 
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, prior to 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 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). Only participants whose suicidal ideation is passive, who expressly deny any intent 
to act, and who, after evaluation, are not judged to be at serious risk for self-harm during the 
study may continue in the study; other participants must be discontinued from study 
participation and receive appropriate clinical follow-up care to ensure their safety. In 
addition, all AEs of suicidal ideation or behavior must be recorded as an ECI (See Section 
8.4.7). Sites are to designate which health care professionals are to be responsible for acute 
care on-site and to specify referral center(s) to be used for further evaluation.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation/randomization, must be reported by the investigator for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment, or a procedure.
From the time of intervention allocation/randomization through 14 days following 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 of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.       
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
Nonserious 
Adverse Event 
(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
Serious Adverse 
Event (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/Lactati
on Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
This section is not applicable.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Disease related events and or disease related outcomes not qualifying as AEs or SAEs are not 
applicable to this study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
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Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this study.
3. Suicidal ideation and/or suicidal behavior. A supplemental document will be provided 
that contains guidance for additional information to be collected and reported for these 
events (Appendix 12).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the trial exceeding the dose prescribed by the protocol. It is up to the investigator or 
the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of PK/PD 
will be collaboratively determined by the Sponsor (eg, samples at lower doses may not be 
assayed if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-1942
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations manual.
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8.7
Pharmacodynamics
PD parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA: 

Blood for Genetic Analysis.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover main study plasma from MK-1942 assay will be stored for future research
•
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Within approximately 5 weeks prior to intervention allocation/randomization, potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should be 
conducted if more than 35 days have elapsed between the participant’s initial screening and 
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planned randomization. Rescreening should include all screening procedures listed in the 
SoA, including consent review.
 
Rescreen procedures cannot be 
conducted the day prior to intervention allocation/randomization if there are Day -1 
procedures planned per protocol.
8.10.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, 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
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, taking the blood sample for MK-1942 is the critical procedure.
At any post-dose time point, the blood sample for MK-1942 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 prior 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 Table 10.
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Table 10
Pharmacokinetic Sample (Blood) Collection Windows
PK Collection
PK Collection Window
0 - <1 hr
5 min
1 - <24 hr
15 min
24 - <48 hr
1 hr
48 - 72 hr
2 hr
•
Predose standard safety evaluations: 
o
Vital signs within 3 hrs prior to dosing
o
ECGs within 1 hour prior to dosing
o
Laboratory safety tests and physical exam within 24 hrs prior to dosing
•
Postdose standard safety evaluations: vital signs, laboratory safety tests, targeted
neurological exam, physical exam, and C-SSRS 
a.
<24 hr postdose: may be obtained within 30 minutes before and 1 hr after the 
stated monitoring time.
b. 24 hr - <48 hr postdose: may be obtained within 4 hr of the stated monitoring 
time.

Post-dose ECG evaluations
o
<24 hours post-dose: should be taken within 15 minutes of stated recording time.
o
24 hours post-dose: should be taken within 1 hour of stated recording time.

Study drug administration: ± 30 mins of stated administration period (AM, PM) and ± 30 
minutes of previous day’s administration times for a given participant.
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-1942 in humans, and the PK, PD, and safety profiles of 
the compound is 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.
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•
Repeat of or decrease in the dose of the study intervention administered in any
given period/panel
•
Interchange of doses between panels
o
Entire period(s) or panel(s) may be omitted
o
Decrease in the duration (eg, number of days) of study intervention administration
o
Adjustment of the dosing interval (eg, divided doses [BID to QD, QD to BID, or
vice versa])
o
Instructions to take study intervention with or without food or drink may also be
modified based on newly available data
o
Modification of the PK sample processing and shipping details based on newly
available data
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK 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.
Up to additional 50 mL of blood may be drawn for safety and/or PK analyses. The total 
blood volume withdrawn from any single participant will not exceed the maximum allowable 
volume during his/her participation in the entire study (Section 8).
The timing of procedures for assessment of safety procedures (eg, VS, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study file and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section contains a summary of the statistical analyses for this trial. Full detail is in the 
Statistical Methods (Section 9.6).
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9.1
Statistical Analysis Plan Summary
Safety
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or 
vital signs as well as for change from baseline, as deemed clinically appropriate. Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline).
Frequency and severity of subjective reports of AEs over the dosing period will be closely 
monitored and reported. The counts and frequency of AEs will be summarized by treatment.  
In addition, posterior probabilities (PP) of the incidence of dizziness, nausea, emesis after co-
administration of MK-1942 and donepezil to AD patients that are less than a target rate will 
be provided.  Such analyses may also be provided for other AEs identified during the study. 
The target rate is determined from the incidence of an AE associated with MK-1942 alone
from MK-1942 P004, and the maximum tolerable increase in the incidence of an AE.  For 
example, if the true AE rate of MK-1942 alone is 40% and the maximum tolerable increase 
in AE incidence associated with MK-1942 + donepezil compared to MK-1942 alone is 20%, 
the target rate would be 60%. A posterior probability greater than 60% will be considered as 
tolerable. 
Responses to the C-SSRS will be tabulated and the individual score > 0 will be listed. The 
difference from pre-treatment baseline values will also be determined.
Pharmacokinetics
Model-based PK Summary
Evaluation of the effects of donepezil on the PK of MK-1942 in AD patients
At each dose level, individual values of the plasma Cmax of MK-1942 on the last day of a 
titrated treatment regimen after co-administration of MK-1942 with donepezil to AD 
patients, as well as the Cmax of MK-1942 after administration of MK-1942 alone to HEV in 
MK-1942-004 will be natural log transformed and analyzed in an ANOVA model. The 
model contains one factor for treatment (MK-1942 alone in HEV, MK-1942+donepezil in 
AD patients). 
Ninety percent (90%) CIs will be constructed for GMRs (MK-1942 + donepezil in AD 
patients/ MK-1942 alone in HEV) from the model after back-transformation. The hypothesis 
that the plasma Cmax of MK-1942 determined on the last day of a titrated treatment regimen 
(Day 21 [28]) when co-administered with donepezil to AD patients is similar to the Cmax 
obtained following administration of MK-1942 alone to HEV (MK-1942-004) will be 
supported if the 90% CI for the true GMR (MK-1942 + donepezil in AD / MK-1942 alone in 
HEV) is contained within the interval (0.5, 2.0).  Ninety-five percent (95%) CIs for the least 
squares means by treatment will be constructed on the natural log scale and will reference a t-
distribution. Exponentiating the least square means and the lower and upper limits of these 
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confidence intervals will yield estimates for the population geometric means and confidence 
intervals about the geometric means on the original scale. Similar analyses will be conducted 
with MK-1942 AUC0-12 and Ctrough. 
Evaluation of the effects of MK-1942 on the PK of donepezil in AD patients
Separately for each PK parameter, individual AUC0-24 and Cmax of donepezil after co-
administration of MK-1942 and donepezil, or donepezil alone (Day -1) will be natural log 
transformed and analyzed in linear mixed effect model. The model contains fixed effect for 
treatment (MK-1942 and donepezil, donepezil alone) and random effect for subject. Ninety-
five percent (95%) CIs for the least squares means by treatment will be constructed on the 
natural log scale and will reference a t-distribution. Ninety percent (90%) CIs will be 
constructed for the true GMRs (MK-1942 + donepezil / donepezil alone) from the model
after back-transformation.
Power
PK:
The estimated pooled, between-subject standard deviations on a log scale for MK-1942 
Cmax on the last day of dosing following administration of 3-mg to 20-mg BID doses of 
MK-1942 for 5 to 10 days to healthy adults in MK-1942-002 is 0.225. Assuming the standard 
deviation is 30% higher in AD patients than HEV (ie, the between-subject standard deviation 
on a log scale for Cmax is 0.29 in AD patients), if the true GMR (MK-1942+donepezil in AD 
patients/MK-1942 alone in HEV) is 1.00, with 18 AD patients receiving MK-1942 and 
donepezil and 6 HEV receiving MK-1942 alone in MK-1942-004, there is a 99% probability 
that the 90% CI of the GMR will fall within the interval of (0.5, 2.0).  
Safety:
With 18 AD patients receiving MK-1942 + donepezil and a target rate of 80%, if the true AE 
rate following administration of MK-1942 + donepezil in AD patients is 60%, there is a 
probability of 97% that co-administration of MK-1942 with donepezil is considered safe and 
tolerable.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or underthe 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Pharmacology Department of the Sponsor.
If changes are made to the statistical analysis plan as outline below after the study has begun,
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the Clinical Study Report.
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9.3
Hypotheses/Estimation
Hypotheses

The plasma Cmax of MK-1942 determined on the last day of a titrated treatment 
regimen (Day 21 [28]) when co-administered with donepezil to AD patients is similar 
to the Cmax obtained following administration of MK-1942 alone to HEV in MK-
1942-004. That is, the true GMR (MK-1942 + donepezil in AD / MK-1942 alone in 
HEV) is contained within the interval (0.5, 2.0).
Estimations

The GMRs of plasma PK parameters (AUC0-24 and Cmax) for those treated with 
MK-1942+ donepezil versus donepezil alone in AD patients will be estimated. 
9.4
Analysis Endpoints
Primary Endpoints
1. Safety: AEs, vital signs, electrocardiograms, clinical chemistry, hematology, 
urinalysis, targeted neurological exams, Columbia suicide severity rating
scale.
Baseline is defined as the pre-dose measurement at Day 1.
Secondary Endpoints
1. Pharmacokinetics: the plasma PK parameters of MK-1942 after administration of 
MK-1942 + donepezil - Cmax, Tmax, Ctrough, AUC0-12, AUC0-24 (days 21 
and 28), and CLss/F (days 21 and 28), Vzss/F (days 21 and 28), apparent terminal 
t1/2 (Daylast – 21 or 28 only).
2. Pharmacokinetics: the plasma PK parameters of donepezil after administration of 
donepezil alone and donepezil + MK-1942 (Days -1, 21, and 28) - Cmax, Tmax, 
and AUC0-24.
Exploratory Endpoints:
1. MMSE-2 and DSST scores obtained at baseline (screening) and from the last 
day of dosing.
2. 12-lead ECG parameters
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (ASasT): The All Subjects 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.
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Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will 
be likely to exhibit the effects of treatment, according to the underlying scientific model.
Compliance covers such considerations as exposure to treatment, availability of 
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 dose level will be included in the 
Per-Protocol dataset. This population will be used for the PK analyses.
9.6
Statistical Methods
9.6.1
Safety
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or 
vital signs as well as for change from baseline, as deemed clinically appropriate. Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline).
The frequency and severity of subjective reports of AEs over the dosing period will be 
closely monitored and reported. The counts and frequency of AEs will be summarized by 
treatment.  In addition, posterior probabilities (PP) of the incidence of dizziness, nausea, 
emesis after co-administration of MK-1942 and donepezil to AD patients that are less than a 
target rate will be provided.  Such analyses may also be provided for other AEs identified 
during the study. The target rate is determined from the incidence of an AE associated with 
MK-1942 alone from MK-1942 P004, and the maximum tolerable increase in the incidence 
of an AE.  For example, if the true AE rate of MK-1942 alone is 40% and the maximum 
tolerable increase in AE incidence associated with MK-1942 + donepezil compared to MK-
1942 alone is 20%, the target rate would be 60%. A posterior probability greater than 60% 
will be considered as tolerable. 
Responses to the C-SSRS will be tabulated and the individual score > 0 will be listed. The 
difference from pre-treatment baseline values will also be determined.
9.6.2
Pharmacokinetics
Model-based PK Summary
Evaluation of the effects of donepezil on the PK of MK-1942 in AD patients
At each dose level, individual values of the plasma Cmax of MK-1942 on the last day of a 
titrated treatment regimen after co-administration with donepezil to AD patients, as well as 
the Cmax of MK-1942 after administration of MK-1942 alone to HEV in MK-1942-004 will 
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be natural log transformed and analyzed in an ANOVA model. The model contains one 
factor for treatment (MK-1942 alone in HEV, MK-1942+donepezil in AD patients). 
Ninety percent (90%) CIs will be constructed for GMRs (MK-1942 + donepezil in AD 
patients/ MK-1942 alone in HEV) from the model after back-transformation. The hypothesis 
that the plasma Cmax of MK-1942 determined on the last day of a titrated treatment regimen 
(Day 21 [28]) when co-administered with donepezil to AD patients is similar to the Cmax 
obtained following administration of MK-1942 alone to HEV (MK-1942-004) will be 
supported if the 90% CI for the true GMR (MK-1942 + donepezil in AD / MK-1942 alone in 
HEV) is contained within the interval (0.5, 2.0).  Ninety-five percent (95%) CIs for the least 
squares means by treatment will be constructed on the natural log scale and will reference a t-
distribution. Exponentiating the least square means and the 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. Similar analyses will be conducted 
with MK-1942 AUC0-12 and Ctrough. 
Evaluation of the effects of MK-1942 on the PK of donepezil in AD patients
Separately for each PK parameter, individual AUC0-24 and Cmax of donepezil when co-
administered with MK-1942 or alone (Day -1) will be natural log transformed and analyzed 
in a linear mixed effects model. The model contains fixed effect for treatment (MK-1942 and 
donepezil, donepezil alone) and random effect for subject. Ninety-five percent (95%) CIs for 
the least squares means by treatment will be constructed on the natural log scale and will 
reference a t-distribution. Ninety percent (90%) CIs will be constructed for the true GMRs 
(MK-1942 + donepezil / donepezil alone) from the model after back-transformation.
Descriptive Statistics
Individual values will be listed for each PK parameter by dose level, and the following (non-
model-based) descriptive statistics will be provided, if appropriate: N (number of participants 
with non-missing data), arithmetic mean, standard deviation, arithmetic percent CV 
(calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as 100 x sqrt(exp(s2) - 1), where s2 is 
the observed variance on the natural log-scale).
Exploratory Analysis
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 provided for the MMSE-2 
scores obtained at baseline (screening) and from the last day of dosing.
WAIS-R 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 provided for the DSST 
scores obtained at baseline (Day -1), Day 14, and from the last day of dosing (Day 21 [28])
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Concentration-QTc
The average of the triplicate measurements at any time point will be calculated prior to any 
further analysis. Fridericia’s correction to QT (QTcF = QT / RR1/3) will be made in order to 
correct for heart rate. The appropriateness of the correction factor (ie, 1/3) will be assessed 
via a linear mixed effects model with QTcF as the response variable and RR interval as a 
covariate and subject as a random effect, using data from the placebo treatment and the 
predose measurements of the active treatments. A slope estimate close to zero would indicate 
that Fridericia's correction provides an adequate correction to the original QT data; 
otherwise, an appropriate transformation on RR will be further explored.
The predose value on Day 1 will serve as baseline for calculating individual change from 
baseline at each time point. Observed plasma concentrations and observed QTcF change 
from baseline will be used to investigate the relationship between QTcF and plasma MK-
1942 concentrations (placebo data will also be used in this assessment, with the plasma 
concentration of MK-1942 set to 0). Scatter plots of QTcF change from baseline versus 
corresponding time-matched MK-1942 concentration will be provided.
The QTcF change from baseline will be further evaluated using a linear mixed effects model 
with fixed effects for treatment (MK-1942, placebo), time point, continuous effects for QTcF 
baseline, plasma concentration. A double compound symmetry covariance structure will be 
assumed. The highest ‘safe’ drug concentration (C_safe), defined as the highest drug 
concentration whose upper limit of the two-sided 90% confidence interval (equivalent to a 
one-sided upper 95% confidence limit) of ΔΔQTcF (placebo- baseline- adjusted) less than 10 
milliseconds (ms), will be reported. An estimate of the expected mean effect and 90% 
confidence interval of ΔΔQTcF will also be computed at the observed geometric mean Cmax 
for each MK-1942 dose of interest.
Additional modeling of the concentration and QTc data from this study may be conducted 
later as part of a broader evaluation of MK-1942's QTc prolongation potential. In that case, a 
separate Modeling Analysis Plan will be written prior to analysis.
9.6.3
General
For all analyses, data will be examined for departures from the assumptions of the statistical 
model(s) as appropriate; eg, heteroscedasticity, non-normality of the error terms.
Distribution-free methods may be used if a serious departure from the assumptions of the 
models(s) is observed, or suitable data transformations may be applied.
9.7
Interim Analyses
No interim analysis is scheduled.
9.8
Multiplicity
Since there is no primary hypothesis, no adjustments for multiplicity are needed.
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9.9
Sample Size and Power Calculations
PK:
The estimated pooled, between-subject standard deviations on log scale for MK-1942 Cmax 
on the last day of dosing following administration of 
 BID doses of MK-1942 
for 5 to 10 days in healthy subjects in MK-1942-002 is 0.225. Assuming the standard 
deviation is 30% higher in AD patients than HEV, i.e. the between-subject standard deviation 
on a log scale for Cmax is 0.29 in AD patients, if the true GMR (MK-1942+donepezil in AD 
patients/MK-1942 alone in HEV) is 1.00, with 18 AD patients receiving MK-1942 and 
donepezil and 6 HEV receiving MK-1942 alone in MK-1942-004, there is 99% probability 
that the 90% CI of the GMR will fall completely within the interval of (0.5, 2.0).  
Safety:
With 18 AD patients receiving MK-1942 + donepezil and a target rate of 80%, if the true AE 
rate following administration of MK-1942 + donepezil in AD patients is 60%, there is a 
probability of 97% that the coadministration of MK-1942 and donepezil is considered safe 
and tolerable (Table 11).
Table 11
Operating Characteristics for a One AE Incidence Rate
Number of Subjects 
Receiving MK-1942 + 
Donepezil
True 
Rate
Target 
Rate
Operating Characteristics
“Go” means tolerable
“Go” if PP (AE rate ≤Target rate)> 60%
Probability of 
“Go”
Probability of 
“No Go”
18
90%
80%
10%
90%
80%
80%
51%
49%
70%
80%
83%
17%
60%
80%
97%
3%
18
70%
60%
14%
86%
60%
60%
44%
56%
50%
60%
77%
24%
40%
60%
95%
5%
CCI
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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.
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 fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to 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 
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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 International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 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.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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 signed ICF, 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 
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the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 12 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 12
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
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
[nonfasting]
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
[Serum or urine] [alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) if applicable]
•
[Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)]  [if applicable]
NOTES: NOTES:
• Urea is acceptable if BUN is not available as per institutional standard.
• WBC Differential: Consider if results providing the absolute or % value will be acceptable or if absolute 
values are required.
• Creatinine: GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
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.
o
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 pre-existing condition that has not 
worsened is not an SAE.) A pre-existing 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.
o
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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•
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.
o
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
o
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
- Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
- Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
- Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
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- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
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 his/her 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.
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•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This section is not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
• Progestogen-only subdermal contraceptive implantb,c
• Intrauterine hormone-releasing systems (IUS)c,d
• Non-hormonal IUD
• Bilateral tubal occlusion
• Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    Male condoms must be used in addition to hormonal contraception.
d    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d.
DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific
analysis is performed will be reported to the Sponsor.
6.  Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonization [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
This appendix is not applicable for this study.
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10.8
Appendix 8: Approximate Blood Volume Table
Test
Pre-study
Treatment Periods
Post-study
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests
2
6
1
9
12.5
112.5
HIV/Hepatitis Screen  
1
1
5
5
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for plasma MK-1942
54
54
4
216
Blood for plasma donepezil
18
18
4
72
Total Blood Volume per Participanta
416.5 mL
a
If additional pharmacokinetic, pharmacodynamic and/or safety analysis is necessary, additional blood (not to exceed 
50 mL) may be obtained.
CCI
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
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
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
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)
Incomplete Right BBB (ICRBBB) 
(QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or 
P Pulmonale
Definite Evidence of P Mitrale or P
Pulmonale
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
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 Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The participant may be excluded from the study;
2.
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).
3.
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
4.
The abnormal test may be repeated (refer items a. and b. 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 General and Targeted Neurological Exams
The General and Targeted Neurological Examination will be performed at the time points 
specified in the Schedule of Activities (Section 1.3).
Note to the investigator: If at any time abnormalities are observed in the General or 
Targeted Neurological Exams, the Investigator should do additional examinations as 
needed based on his or her medical judgment.
The General Neurological Examination
The General Neurological Examination includes all of the modules listed below and is 
intended to be a general screening examination.
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example difficulty remembering or following 
instructions or distractibility may be signs of inattention)
B. Thought Processes and Language (generally assess logic, relevance, organization and 
coherence of volunteer’s use of language throughout the interview).
C. Orientation (time, place, person).
D. Attention/Concentration
Ask the 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 one error.
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MODULE 2 – CRANIAL NERVE ASSESSMENT
A. II – Eyesight 
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus).
1. Observe for nystagmus during eye movements, increased nystagmus at the 
end of gaze or other oculomotor changes (mild nystagmus at extremes of gaze 
is normal). Note direction of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test eg by rubbing fingers on 
each side of 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
MODULE 3 - MOTOR SYSTEM
A. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows and knees (bilaterally).
3. There is a small, continuous resistance to passive movement.
4. Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score: left and right
Grade: NORMAL, INCREASED or DECREASED
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B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
2. Test proximal limb strength by having the volunteer flex and extend the knees and 
elbows against your resistance.
Test bilaterally and compare one side to the other.
Score: left and right
Grade: 5/5: normal; 
4/5: movement against resistance impaired; 
3/5: movement against gravity but not against resistance; 
2/5: visible movement but not against gravity; 
1/5: visible contraction; 
0/5: no visible activity
3. Test distal limb strength by having the volunteer conduct dorsiflexion and plantar 
flexion of the volunteer’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally and compare one side to the other.
Score: left and right
Grade: 5/5: normal; 
4/5: movement against resistance impaired; 
3/5: movement against gravity but not against resistance; 
2/5: visible movement but not against gravity; 
1/5: visible contraction; 
0/5: no visible activity
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C. Pronator Drift
1. Ask the volunteer to hold both arms straight forward with, palms up and eyes 
closed for ≈10-15 seconds as tolerated; watch for how well the arm position is 
maintained.
2. Instruct the volunteer to keep both arms still while you tap them briskly downward.
The volunteer should normally be able to maintain extension and supination. Inability 
to maintain extension and supination (and drift into pronation) indicates an upper 
motor neuron deficit.
Score: left and right
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 4 - REFLEXES
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at Investigator's discretion (eg 
elbow, wrist or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip 
of each finger, in sequence, as fast as possible.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the participant will 
be asked to strike his hand on the thigh, raise the hand, turn it over and then 
strike the back of the hand down on the same place. (This test is impaired in 
cerebellar disease, extra pyramidal disease and upper MN weakness.)
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B. Point-to-Point Movements
1. Ask the volunteer to touch your index finger and their nose alternately several 
times. Move your finger about as the volunteer performs this task.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the point-to-point testing is disturbed, the 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 volunteer to stand with both feet together and eyes closed for 20 to 30 
seconds without support.
2. Be prepared to catch the volunteer if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the volunteer to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Vibration: tuning fork vibration detection in hands, feet bilaterally.
D. Stereognosis: (identify common objects placed in hand, eg, coin, key).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A 
to F)
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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:
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)
MODULE 2 – CRANIAL NERVE ASSESSMENT
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
MODULE 3 - MOTOR SYSTEM
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
MODULE 5 - GAIT
B. Gait
1. Ask the volunteer to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
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10.12 Appendix 12: Additional Information to be Collected from Subjects Who Report 
Suicidal Ideation and/or Behavior
Adverse events of suicidal ideation and/or behavior must be reported to Merck as an Event of
Clinical Interest (ECI) within 24 hours of observation. Suicidal ideation and behavior may be 
identified through spontaneous participant reports and/or upon review of the C-SSRS 
responses or other assessment tools.
Participants who at any time during this study spontaneously report AEs of suicidal ideation 
or behavior, either as an outpatient or during visit interviews, or whose responses to the 
QIDS-SR16 (when assessed) or C-SSRS are suggestive of suicidal ideation and behavior, 
must be assessed by the investigator and referred for further mental health evaluation. 
Participants with treatment-emergent suicidal ideation and/ or behavior must be evaluated 
that day by a psychiatrist or other trained mental health professional who is a licensed 
psychologist, social worker or nurse practitioner (or comparable professional qualification in 
countries outside the United States). Only patients whose suicidal ideation is passive, who 
expressly deny any intent to act, and who, after evaluation, are not judged to be at serious 
risk for self-harm during the course of the study may continue in the study; others must be 
discontinued from study participation and receive appropriate clinical follow-up care to 
assure their safety.
The investigator will collect the following information, in addition to any other relevant 
information deemed appropriate by the investigator or Sponsor. It is important to also note 
pertinent negatives where applicable to convey that the information was collected. This 
information must be entered in INFORM in narrative format in the Adverse Experience free 
text fields. These data will be used to provide a narrative summary of the event.
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
AE
adverse event 
ALT
Alanine aminotransferase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
APaT
All-Participants-as-Treated
AST
Aspartate aminotransferase
ATD
accelerated titration design
AUC
area under the plasma concentration-time curve
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
BT
body temperature
CI
confidence interval
CG
Cockcroft-Gault
CNS
central nervous system 
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
Cmax
maximum plasma concentration
CrCl
creatinine clearance
CRF
case report form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
C-SSRS/SLA
C-SSRS since last assessment
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 4.0
Common Terminology Criteria for Adverse Events, Version 4.0
Ctrough
trough plasma concentration
D
day
DBP
diastolic blood pressure
DFC
dry filled capsule
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
F
fluoride
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
good clinical practice 
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
CCI
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Abbreviation
Expanded Term
HBV
hepatitis B virus
HCl
hydrochloride
HEV
healthy elderly volunteer
HIV
human immunodeficiency virus
hr
hour
HR
heart rate
IB
Investigator’s Brochure 
ID/pbo
investigational drug/placebo
ICF
informed consent form
ICH
International Council on Harmonization
IEC
Institutional Ethics Committee
IMP/NIMP
Investigational/Non-Investigational Medicinal Product
IND
Investigational New Drug 
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
NCS
not clinically significant
NDA
New Drug Application 
nH
Hill coefficient
NOAEL
no observed adverse effect level 
Occ50
compound concentration resulting in 50% occupancy of a receptor
OSF
on-site formulation
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetic
PO
orally
PP
per-protocol
QD
Quaque die (daily)
QTc
corrected QT interval
RNA
ribonucleic acid
RO
receptor occupancy
RR
respiratory rate
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
tmax
time to maximum plasma concentration
UDS
urine drug screen
V 
volume of distribution
VS
vital sign
WAIS
Wechsler adult intelligence scale
WBC
white blood cell
WONCBP
woman/women of non-childbearing potential 
CCI
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REFERENCES
[O'Keeffe, S. T., et al 
1996]
O'Keeffe ST, Kazeem H, Philpott RM, Playfer 
JR, Gosney M, Lye M. Gait disturbance in 
Alzheimer's disease: a clinical study. Age 
Ageing. 1996;25:313-6.
05DHHF
[Jackson, S., et al 2004]
Jackson S, Ham RJ, Wilkinson D. The safety and 
tolerability of donepezil in patients with 
Alzheimer's disease. Br J Clin Pharmacol. 
2004;58(S1):1-8.
05DHHD
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