Conditions: Alzheimer's Disease Mild Cognitive Impairment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
The main purpose of this study is to assess the ability of a repeated high-frequency site-based computerized cognitive assessment to evaluate the potential treatment effects of donepezil (MK-0000) compared with placebo among participants with mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD). The primary study hypothesis is that the average percentage of correct responses on one card learning (OCL) task will be ≥2 percentage points in participants receiving donepezil compared with participants receiving placebo.

Detailed description:

Arms:
arm 1: Participants receive donepezil in doses up to 10 mg once daily (QD), orally in a scheduled titration for Days 1-56. The total treatment duration is 56 days. arm 2: Participants receive placebo QD, orally for Days 1-56. The total treatment duration is 56 Days.

Interventions: intervention 1: Donepezil intervention 2: Placebo
Intervention descriptions: intervention 1: Donepezil 5 mg capsules for a total daily dose of up to 10 mg QD, orally, for Days 1-56. intervention 2: Dose matched placebo capsule QD, orally for Days 1-56.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT04730635
Document Date:           02-Dec-2022
A Clinical Study to Evaluate a Cognitive
Platform to Support Development
of Symptomatic Therapies in Participants at
Risk for Alzheimer’s Disease


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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 LLC, RAHWAY, NJ USA (MSD).
Protocol Title: A Clinical Study to Evaluate a Cognitive Platform to Support Development 
of Symptomatic Therapies in Participants at Risk for Alzheimer’s Disease
Protocol Number: 413-05
Compound Number: MK-0000
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
137,207
Approval Date: 02 December 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
02-DEC-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in 
an entity name change and update to the address. 
Amendment 04
30-SEP-2021
Modify inclusion criterion #2a by changing CDR Sum of Boxes score from “at 
least 3.5” to “at least 2.0” when the Global CDR is 0.5 for participants diagnosed 
with MCI.
Amendment 03
21-JUN-2021
Adjustments made to exclusion criteria to support enrollment.
Amendment 02
02-MAR-2021
Modify exclusion criterion #26 by shortening the exclusionary period for previous 
neuropsychological testing from 6 months to 4 weeks to support enrollment of 
participants who have been recently diagnosed with cognitive impairment or 
Alzheimer’s disease.
Amendment 01
13-NOV-2020
Addition of ECG (and/or review of ECG report from 3 months prior) as a 
screening procedure to ensure enrollment of participants with no contraindication 
to donepezil
Original Protocol
30-SEP-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
Section 5.2 Exclusion 
Criteria
Exclusion Criteria #6 – addition of “with
Sponsor’s approval” to the note: 
Note: Participants with a score of 5 or 
more who are not diagnosed with major 
depression following such an assessment 
may be included in the study with 
Sponsor’s approval.
Clarification on when such participants may be included 
in the study
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Section # and Name
Description of Change 
Brief Rationale 
Section 5.2 Exclusion 
Criteria
Section 10.10 Appendix 10: 
Abbreviations
Exclusion Criteria #11 – addition of the 
following exception: “Participants with a 
history of chronic hepatitis C infection
with a documented cure and/or a positive 
serologic test for HCV with a negative 
HCV viral load may be included following 
Sponsor consultation.”
Addition of HCV to list of abbreviations
Exception added to support enrollment of participants 
diagnosed with AD who have been treated for hepatitis C 
with no active infection
Section 5.2 Exclusion 
Criteria
Exclusion Criteria #15 – Table 2 
Prohibited Medications: For 
Analgesics/Narcotics, change the 
prohibited duration from “24-48 hrs” to 
“48 hrs” in the corresponding Notes 
column so that the exception now reads: 
“Exception: if dosing is ≤ 2 doses/week 
(i.e. not regularly used) this is acceptable. 
Prohibited 48 hrs before study visits. 
Update made to remove ambiguity with respect to the 
duration when the medication is prohibited prior to study 
visits
Section 5.2 Exclusion 
Criteria
Exclusion Criteria #15 – Table 2 Prohibited 
Medications: addition of “Selected” to 
“Herbal Supplements/Vitamins” in the 
Prohibited Medications column and addition 
of “/vitamins” in the corresponding Notes 
columns to read “other herbal 
supplements/vitamins”.
Clarification added noting that not all herbal 
supplements/vitamins are exclusionary and to contact 
Sponsor with questions on other herbal 
supplements/vitamins that are not listed
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Section # and Name
Description of Change 
Brief Rationale 
Section 5.2 Exclusion 
Criteria
Exclusion Criteria #26 – inclusion of the 
MMSE as an example: “Has undergone 
neuropsychological testing (including the 
MMSE) or cognitive remediation in the 
past 4 weeks.”
Clarification that the MMSE is considered a 
neuropsychological assessment
Section 8.10 Visit 
Requirements
First paragraph describing the scheduling 
of the 3 visits for each testing period: 
change from “should be scheduled” to 
“must be scheduled”. 
Correct grammar by adding “should” in 
this sentence: “Preferably, each cluster of 
3 clinic visits should be scheduled . . .” 
Revisions to emphasize the importance of scheduling the 
visits together in order to cluster them for each 5-
consecutive days testing period and to align with the 
footnotes detailing this requirement in Sec 1.3 Schedule 
of Activities
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
In Table 11, under “Other Screening 
Tests”:  separation of homocysteine and 
MMA from Vitamin B12 and folate as 
follows:
• Vitamin B12, Folate (Homocysteine and 
MMA are required in case of Vitamin B12 
and/or folate deficiency)
Clarification that homocysteine and methylmalonic acid
tests are supplemental and only required for eligibility 
evaluation in case of vitamin B12 and/or folate 
deficiency
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................28
2.1
Study Rationale....................................................................................................28
2.2
Background ..........................................................................................................28
2.2.1
Information on Study-Related Therapy .......................................................28
2.3
Benefit/Risk Assessment......................................................................................29
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................32
4.1
Overall Design......................................................................................................32
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................36
4.2.1.1
Efficacy Endpoints.............................................................................36
4.2.1.2
Safety Endpoints................................................................................36
4.2.1.3
Pharmacokinetic Endpoints ...............................................................36
4.2.1.4
Pharmacodynamic Endpoints.............................................................36
4.2.1.5
Planned Exploratory Biomarker Research.........................................39
4.2.1.5.1
Planned Genetic Analysis ........................................................39
4.2.1.5.2
Exploratory Plasma Diagnostic Biomarkers for 
Alzheimer’s Disease ................................................................39
4.2.1.6
Future Biomedical Research..............................................................40
4.2.2
Rationale for the Use of Placebo .................................................................40
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................40
4.3
Justification for Dose...........................................................................................40
4.4
Beginning and End of Study Definition .............................................................41
4.4.1
Clinical Criteria for Early Study Termination .............................................41
5
STUDY POPULATION ................................................................................................41
5.1
Inclusion Criteria.................................................................................................42
5.2
Exclusion Criteria................................................................................................44
5.3
Lifestyle Considerations......................................................................................50
5.3.1
Meals and Dietary Restrictions....................................................................50
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................50
5.3.2.1
Caffeine Restrictions..........................................................................50
5.3.2.2
Alcohol Restrictions...........................................................................50
5.3.2.3
Tobacco Restrictions..........................................................................51
5.3.3
Activity Restrictions ....................................................................................51
5.4
Screen Failures.....................................................................................................51
5.5
Participant Replacement Strategy......................................................................51
6
STUDY INTERVENTION............................................................................................52
6.1
Study Intervention(s) Administered...................................................................52
6.2
Preparation/Handling/Storage/Accountability .................................................54
6.2.1
Dose Preparation..........................................................................................54
6.2.2
Handling, Storage, and Accountability........................................................54
6.3
Measures to Minimize Bias: Randomization and Blinding..............................55
6.3.1
Intervention Assignment..............................................................................55
6.3.2
Stratification.................................................................................................55
6.3.3
Blinding........................................................................................................55
6.4
Study Intervention Compliance..........................................................................56
6.5
Concomitant Therapy..........................................................................................56
6.5.1
Rescue Medications and Supportive Care ...................................................58
6.6
Dose Modification/Titration................................................................................58
6.7
Intervention After the End of the Study............................................................58
6.8
Clinical Supplies Disclosure................................................................................58
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................59
7.1
Discontinuation of Study Intervention...............................................................59
7.2
Participant Withdrawal From the Study...........................................................60
7.3
Lost to Follow-up .................................................................................................60
8
STUDY ASSESSMENTS AND PROCEDURES........................................................60
8.1
Administrative and General Procedures ...........................................................61
8.1.1
Informed Consent.........................................................................................61
8.1.1.1
General Informed Consent.................................................................61
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................62
8.1.2
Inclusion/Exclusion Criteria ........................................................................62
8.1.3
Participant Identification Card.....................................................................62
8.1.4
Medical History ...........................................................................................63
8.1.5
Prior and Concomitant Medications Review...............................................63
8.1.5.1
Prior Medications...............................................................................63
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8.1.5.2
Concomitant Medications..................................................................63
8.1.6
Assignment of Screening Number...............................................................63
8.1.7
Assignment of Treatment/Randomization Number.....................................63
8.1.8
Study Intervention Administration ..............................................................64
8.1.8.1
Timing of Dose Administration.........................................................64
8.1.9
Discontinuation and Withdrawal .................................................................64
8.1.9.1
Withdrawal From Future Biomedical Research ................................65
8.1.10
Participant Blinding/Unblinding..................................................................65
8.1.11
Calibration of Equipment.............................................................................66
8.1.12
Rater Expectations and Training for Clinical and Cognitive 
Assessments.................................................................................................66
8.1.13
Modified Hachinski Ischemia Scale ............................................................67
8.1.14
Mini Mental State Examination...................................................................67
8.1.15
Clinical Dementia Rating Scale...................................................................67
8.1.16
Geriatric Depression Scale  – 15 Item .........................................................67
8.1.17
Magnetic Resonance Imaging......................................................................67
8.1.18
Domiciling (Optional)..................................................................................67
8.1.19
Participant and Study Partner Questionnaires (Optional)............................68
8.1.20
History of Neuropsychological Assessments...............................................68
8.2
Efficacy Assessments ...........................................................................................68
8.3
Safety Assessments...............................................................................................68
8.3.1
Physical Examinations.................................................................................68
8.3.2
Neurological Examination ...........................................................................69
8.3.3
Vital Signs....................................................................................................69
8.3.3.1
Resting Vital Signs ............................................................................69
8.3.4
Electrocardiograms ......................................................................................69
8.3.5
Clinical Safety Laboratory Assessments .....................................................70
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................70
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................70
8.3.7
Photograph of Rash......................................................................................71
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................71
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................72
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......73
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...74
8.4.4
Regulatory Reporting Requirements for SAE .............................................74
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................74
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................74
8.4.7
Events of Clinical Interest............................................................................75
8.5
Treatment of Overdose........................................................................................75
8.6
Pharmacokinetics.................................................................................................75
8.6.1
Blood Collection for Plasma Donepezil ......................................................76
8.7
Pharmacodynamics..............................................................................................76
8.7.1
Computerized Cognitive Assessments.........................................................76
8.7.2
Free and Cued Selective Reminding Test (FCSRT)....................................77
8.7.3
Wechsler Adult Intelligence Scale (WAIS-IV)-Coding ..............................77
8.7.4
Tests from the Delis-Kaplan Executive Function System (D-KEFS) .........77
8.8
Biomarkers ...........................................................................................................78
8.8.1
Planned Genetic Analysis Sample Collection..............................................78
8.8.2
Exploratory Plasma Biomarkers for Alzheimer’s Disease Diagnosis 
Sample Collection........................................................................................78
8.9
Future Biomedical Research Sample Collection...............................................79
8.10
Visit Requirements...............................................................................................79
8.10.1
Screening (Visits 1-4) ..................................................................................80
8.10.2
Treatment Period (Visits 5-19) ....................................................................82
8.10.3
Poststudy (Visit 20)......................................................................................84
8.10.4
Critical Procedures Based on Study Objectives: Timing of Procedure.......85
8.10.5
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................85
9
STATISTICAL ANALYSIS PLAN .............................................................................86
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses.................................................................................87
9.3
Hypotheses/Estimation ........................................................................................87
9.4
Analysis Endpoints...............................................................................................88
9.5
Analysis Populations............................................................................................88
9.6
Statistical Methods...............................................................................................88
9.7
Interim Analyses ..................................................................................................90
9.8
Multiplicity ...........................................................................................................90
9.9
Sample Size and Power Calculations .................................................................90
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................92
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........92
10.1.1
Code of Conduct for Clinical Trials.............................................................92
10.1.2
Financial Disclosure.....................................................................................94
10.1.3
Data Protection.............................................................................................95
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10.1.3.1
Confidentiality of Data ......................................................................95
10.1.3.2
Confidentiality of Participant Records...............................................95
10.1.3.3
Confidentiality of IRB/IEC Information............................................95
10.1.4
Publication Policy........................................................................................96
10.1.5
Compliance with Study Registration and Results Posting Requirements ...96
10.1.6
Compliance with Law, Audit, and Debarment ............................................96
10.1.7
Data Quality Assurance ...............................................................................97
10.1.8
Source Documents .......................................................................................98
10.1.9
Study and Site Closure.................................................................................98
10.2
Appendix 2: Clinical Laboratory Tests..............................................................99
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................100
10.3.1
Definition of AE ........................................................................................100
10.3.2
Definition of SAE ......................................................................................101
10.3.3
Additional Events Reported.......................................................................102
10.3.4
Recording AE and SAE .............................................................................102
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................106
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................108
10.5
Appendix 5: Contraceptive Guidance..............................................................109
10.5.1
Definitions..................................................................................................109
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................110
10.7
Appendix 7: Country-specific Requirements..................................................115
10.8
Appendix 8: Blood Volume Table ....................................................................116
10.9
Appendix 9: Targeted Neurological Examination ..........................................117
10.10 Appendix 10: Abbreviations .............................................................................118
11
REFERENCES.............................................................................................................120
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LIST OF TABLES
Table 1
Description of Outcome Measures for the Cogstate Battery .....................38
Table 2
Prohibited Medications that Require a Washout Period Prior to 
Completion of Visit 1 (Non-inclusive List)...............................................47
Table 3
Study Interventions....................................................................................53
Table 4
Sample Allocation Schedule......................................................................55
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................73
Table 6
Recommended Order and Timing of Procedures at Visits 3 and 18..........83
Table 7
Recommended Order and Timing of Procedures at Visits 3-4 and 18-
19 if Splitting Visits...................................................................................84
Table 8
Pharmacokinetic (Blood) Collection Windows .........................................85
Table 9
Power Primary Hypothesis ........................................................................87
Table 10
Power associated with Primary Hypothesis...............................................91
Table 11
Protocol-required Safety Laboratory Assessments....................................99
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Clinical Study to Evaluate a Cognitive Platform to Support Development 
of Symptomatic Therapies in Participants at Risk for Alzheimer’s Disease
Short Title: Cognition Platform Study in Participants at Risk for Alzheimer’s Disease
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
The following objectives will be evaluated in participants diagnosed with mild cognitive 
impairment or mild Alzheimer’s Disease.
Primary Objectives
Primary Endpoints
- To assess the ability of a repeated high-
frequency site-based computerized cognitive 
assessment to evaluate the potential treatment 
effects of donepezil compared with placebo 
in participants with MCI/mild AD following 
a limited treatment duration (8 weeks 
treatment).
Hypothesis: After 8 weeks of daily treatment, 
the change from the placebo run-in period 
(Week -1) in average proportion of correct 
responses on the One Card Learning (OCL) 
task (a task of visual learning) in participants 
receiving donepezil compared with 
participants receiving placebo will be ≥2 
percentage points. 
- Proportion of correct responses on the 
OCL task at Weeks -1, 2, 4, 6, and 8
Secondary Objectives
Secondary Endpoints
- To characterize the inter- and intra-subject 
variability associated with repeated high-
frequency site-based computerized cognitive 
test administration in participants with 
MCI/mild AD.
Hypothesis: The overall standard deviation 
associated with the change from the placebo 
run-in period in average OCL repeated 
measurements (arcsine square root 
transformed) after 8 weeks of donepezil 
treatment is ≤ 0.1.
- Proportion of correct responses on the 
OCL task 
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- To assess the ability of a repeated high-
frequency site-based computerized cognitive 
assessment to evaluate the potential treatment 
effects of donepezil after 8 weeks of 
treatment compared to after the placebo run-
in period in participants with MCI/mild AD.
Hypothesis: After 8 weeks of daily treatment 
in participants receiving donepezil, the 
proportion of correct responses in the OCL 
task will improve relative to performance 
during the placebo run-in period by a 
clinically-meaningful (>2 percentage points) 
degree of change.
- Proportion of correct responses on the 
OCL task
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Alzheimer’s Disease
Population
Participants with mild cognitive impairment or mild 
Alzheimer’s Disease
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Single-blind (placebo run-in) followed by double-blind
Blinding Roles
Participants or Subjects, Care Provider, Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 16 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
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Number of Participants:
A sufficient number of participants will be allocated/randomized such that approximately 36
evaluable participants complete the study as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administra-
tion
Treatment 
Regimen
Use
Active
Donepezil 
(Over-
encapsulated)
5mg
QD
Oral
Days 1-14
Experimental
Donepezil 
(Over-
encapsulated)
10 mg
QD
Oral
Days 15-56
Experimental
Placebo
Placebo 
Matching 
Donepezil 
(Over-
encapsulated) 
N/A
QD
Oral
Days 1-56
Experimental
Abbreviations: QD=Once per Day; N/A=Not Applicable
All participants will receive placebo QD during a single-blind ~ 2-week 
run-in period, prior to receiving one of the 2 interventions listed in the 
table above during the 8-week double-blind treatment period. In the 
double-blind period, participants in both Intervention Groups will up-titrate 
following at least 14 days of dosing.
Total 
Number of 
Intervention 
Groups/ 
Arms
2
Duration of 
Participation
Each participant will participate for approximately 15 to 19 weeks from the 
time the participant provides documented informed consent through the 
final contact. After a screening phase ranging from approximately 3-7
weeks, each participant will be receiving assigned intervention for 
approximately 10 weeks: placebo run-in period of approximately 2 weeks, 
followed by double-blind treatment period of 8 weeks). After the end of 
treatment, each participant will be followed for 14 days.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study 
oversight considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Administrative Procedures
Informed Consent – Study 
Participant
X
Section 8.1.1.1
Informed Consent – Study 
Partner/Informant
X
Section 8.1.1.1
Study partner required 
for CDR assessment
Informed Consent for FBR 
(Optional)
X
Section 8.1.1.2
Inclusion/Exclusion Criteria
X
X
X
X
Section 8.1.2; Review 
against criteria in 
Sections 5.1, 5.2.
Participant ID Card
X
Section 8.1.3
Medical History
X
Includes substance 
usage: drugs, alcohol, 
tobacco and caffeine
History of Neuropsychological 
Assessments
X
Section 8.1.20: Any 
testing that may have 
been performed within 
the past 6 months
Prior/Concomitant Medication 
Review
   X------------------------------X
X--------------X
X---------X
X---------------------------------------------------------------X
Section 5.2: 
Table 2
Assignment of Screening 
Number
X
08CSPK


PRODUCT: MK-0000  
20
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Assignment of 
Treatment/Randomization 
Number
X
Prior to dispensing 
first dose of study 
intervention (single 
blind placebo run-in)
Study Intervention (Placebo) 
Dispensing to Study 
Participant/Partner
X
Instruct participant to 
dose with 1 capsule 
per night
Study Intervention 
(Donepezil/Placebo) 
Dispensing to Study 
Participant/Partnerh
X
Xg
X
X
Collect prior 
medication bottle 
before dispensing new 
one. 
Starting Visit 10, 
instruct participant to 
dose 2 capsules per 
night (if medication is 
well tolerated).
Study Intervention Dosing 
Diary Dispensing to Study 
Participant/Partner
X
Study Intervention (At-Home) 
Dose Administration/ Record in 
Diaryh
X---------------X
X---------X
X--------------------------------------------------X
QD dosing, prior to 
retiring, at 
approximately same 
time each night. Last 
dose should be in the 
evening prior to V19.
08CSPK


PRODUCT: MK-0000  
21
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Study Intervention 
Compliance/Diary Review
X
X
X
X
X
Xg
X
X
X
X
X
X
X
X
X
MHIS
X
Section 8.1.13
MMSEi
X
Xd
Section 8.1.14; the 2 
assessments should be 
performed by the 
same rater and 
administered at least 2 
weeks apart.
CDR Scale i,j
X
Section 8.1.15
GDS – 15 Item
X
Section 8.1.16
MRIk
X
Section 8.1.17
Domiciling (Optional)h,l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cognitive Testing to 
be done for 3 
consecutive days if 
kept domiciled
Participant/Study Partner 
Questionnaire (Optional)m
X
Xm
Section 8.1.19; Survey 
regarding Remote 
Cognitive Testing
Safety Procedures
Full Physical Examination
X
X
Section 8.3.1
Height
X
Weight
X
BMI to be taken at 
screening
08CSPK


PRODUCT: MK-0000  
22
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Targeted Neurological 
Examination
X
Section 8.3.2 and 
Appendix 9.
Mental status module 
is covered by MMSE.
Vital Signs (Heart Rate, Blood 
Pressure)
X
X
Section 8.3.3
Respiratory Rate
X
X
Body Temperature
X
X
12-lead ECGn
X
Section 8.3.4
Serum FSH - (as needed in 
postmenopausal females only)
X
Xo
Appendix 5
RPR
X
Appendix 2
HIV, hepatitis B and C screen 
X
Appendix 2
UDS
X
Appendix 2
Hematology
X
X
Appendix 2
Urinalysis
X
X
Appendix 2
Chemistry
X
X
Appendix 2; Includes 
at screening: TSH, 
Vitamin B12, Folate, 
Homocysteine, and 
MMA
AE/SAE review
   X---------------------------X
 X------------X
X--------X
 X-----------------------------------------------------------X
C-SSRS Screening
X
Section 8.3.6
C-SSRS Since Last Visit
X
X
X
X
X
X
X
Section 8.3.6
08CSPK


PRODUCT: MK-0000  
23
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Pharmacokinetics
Blood for Plasma Donepezil 
Assay
X
X
X
Sections 8.6, 8.9 
Pharmacodynamics
Computerized Cognitive 
Assessment with Cogstate Brief 
Batteryp,q
Xp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.7.1: 
Detection (DET), 
Identification (IDN), 
One-Card Learning 
(OCL), One Back 
(ONB)
Computerized Cognitive 
Assessment with additional 
Tests from Cogstate Battery:
Section 8.7.1
International Shopping List 
Test-Learning Trials
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISLT – 12 words
Modified Groton Maze 
Learning Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
GMLTM
Continuous Paired Associate 
Learning
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CPAL
International Daily Symbol 
Substitution Test -Medicines
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IDSSTM
International Shopping List 
Test -Delayed Recall
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISRL- 12 words
Face Name Associative 
Memory Exam
X
X
X
X
X
X
X
X
X
X
X
X
FNAME
08CSPK


PRODUCT: MK-0000  
24
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
Low Frequency Cognitive 
Batteryr: 
Sections 8.7.2, 8.7.3, 
8.7.4
FCSRTs
X
X
Picture version with 
Immediate and 
Delayed Recall
WAIS-IV-Coding
X
X
Verbal Fluency Testt
X
X
D-KEFS subscale
Sorting 
X
X
D-KEFS subscale
Twenty Questions
X
X
D-KEFS subscale
Biomarkers
Blood for Genetic Analysis
X
Sections 8.8, 8.9. 
Collect predose from 
enrolled participants 
only.
Blood for APOE genotyping
X
Sections 8.8, 8.9. 
Collect predose from 
enrolled participants 
only and in a separate 
tube from the sample 
taken for Genetic 
Analysis.
Blood for Exploratory Plasma 
Biomarkers for AD Diagnosis
Xu
X
Sections 8.8, 8.9.
08CSPK


PRODUCT: MK-0000  
25
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
AD=Alzheimer’s Disease; AE=adverse event; APOE=Apolipoprotein E; CDR=Clinical Dementia Rating; C-SSRS=Columbia-Suicide Severity Rating Scale; D-KEFS= Delis-Kaplan Executive 
Function System; ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; FCSRT=Free and Cued Selective Reminding Test; GDS=Geriatric Depression 
Scale; HIV=human immunodeficiency virus; ID=identification; MHIS=Modified Hachinski Ischemia Scale; MMA=methylmalonic acid; MMSE=Mini Mental State Examination; MRI=Magnetic 
Resonance Imaging; RPR=Rapid Plasma Reagin; SAE=serious adverse event; UDS=Urine Drug Screen; WAIS=Wechsler Adult Intelligence Scale
a.
Poststudy visit procedures should also be performed for participants who discontinued early from study intervention.
b.
The 3 visits for each weekly testing period will be scheduled together, with the first 2 visits scheduled within 5 days of the last testing visit in that week. For example, Visits 2 and 3 are 
anchored by the date when Visit 4 is scheduled; they will be scheduled on any one of the 4 days prior to Visit 4 Randomization. Similarly, Visits 5 and 6 are anchored by the date when Visit 7 
is scheduled; they will be scheduled on any one of the 4 days prior to Visit 7. Preferably, each cluster of 3 clinic visits will be scheduled within a single working week (which could include the 
following [not preceding] Saturday if the clinic is open and staffed appropriately). It is recommended that the site schedule all study visits in advance when a participant is deemed eligible 
based on Visit 1 results. If the +3 days permissible study visit window is used for the anchor visit (i.e. third visit of each testing period), the first 2 visits of that testing period will still need to 
occur within 4 days prior to the anchor visit.
c.
Screening Visit 1 assessments may be conducted over the course of more than 1 day to decrease participant/study partner burden (See Section 8.10.1 for details). The visit window for 
Screening Visit 1 is provided to accommodate up to a 30-day washout period for prohibited medications, resolve/stabilize any conditions or treatments, provide flexible scheduling, and repeat 
of study procedures, if needed. If Visit 1 is split for washing out prohibited medications, then the initial portion of Visit 1 would occur on Day -62 and the final portion of Visit 1 will occur on 
Day -32, which is when the clinical and cognitive assessments (MMSE, CDR, MHIS, GDS, and C-SSRS) should be performed.
d.
Visit 2 Baseline/Familiarization is the first clinic visit for the first testing cluster and is anchored by the date when Visit 4 (Randomization) is scheduled; Visits 2 and 3 should be scheduled 
within the 4 days prior to Visit 4. In addition, since MMSE is repeated at Visit 2 following the first screening MMSE, Visit 2 should be scheduled at least 2 weeks from the first Screening visit 
when the first MMSE is performed (see Manual of Assessments [MOA] for details related to alternate words which should be used at Visit 2 to minimize practice effects).
e.
Visit 4 will be scheduled at approximately 2 weeks prior to Study Day 1 (Visit 7), within the permissible window of ±3 days for Visit 4 to occur between Study Day -11 to -17. If the ±3 day 
permissible window is used for Visit 4, then Visits 2 and 3 must still be scheduled within 4 days prior to Visit 4.
f.
Study Day 1 is anchored by the date of the first dose of the double-blind period (in the evening of Visit 7). The Scheduled Week and Study Day in this SoA are to be used as internal reference 
by the sponsor and study site staff when scheduling participant visits. From the participant and study partner’s perspective, they are participating in a single intervention period. Study 
participants should only be aware of the High Frequency Cognitive Testing Period number, Visit number, and the corresponding calendar date the visit falls on.
g.
If Visit 10 is scheduled on Study Day 15, the site should call the day before and ensure patient compliance with QD dosing prior to this visit. If patient has skipped a dose during this 2-week
period, Visit 10 should be rescheduled within permissible window +3, to ensure participants have demonstrated tolerability prior to instructing participants to up-titrate study medications 
following this visit.
08CSPK


PRODUCT: MK-0000  
26
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
h.
For participants who are kept domiciled for the duration of the 3-day testing period, the study staff will witness the dose administration when participants are in the CRU and work with the 
participants on the completion of the study intervention dosing diary. 
i.
The MMSE and CDR should be submitted to the rater training vendor the same day they are administered.
j.
The CDR must be administered by a qualified rater who is not involved with other assessments at Screening Visit 1. The study partner should be interviewed first, followed by the participant 
(see MOA).
k.
Previous scans performed within 1 year of signing ICF may be used in lieu of a screening scan, provided the scans themselves or the report of the scan are made available to the investigator for 
assessment of study eligibility. If a new MRI needs to be performed, it should be scheduled to occur after participant has met all other study eligibility criteria at Visit 1
l.
Only for sites with capability to keep participants overnight and if in the opinion of the investigator and study participant, domiciling is preferable to daily visits to the clinic- in which case the 
3 days of cognitive testing should be on consecutive days. Participants would be discharged after completion of study procedures on the 3rd day of each testing period. The study partner is not 
required to spend the night but may do so depending on the participant.
m.
Participant only completes questionnaire at Visit 13. Both participant and study partner are to complete at Visit 18. If the Low Frequency Cognitive Battery (LFCB) was administered across 2 
days (e.g. Visits 18 & 19), then questionnaire should be administered at Visit 19. The study partner completing the questionnaire should be the same individual that completed the CDR 
assessment at the Screening visit. The study partner portion of the questionnaire maybe completed by phone if he/she did not accompany the study participant to the visit.
n.
Previous ECG performed within 3 months of signing ICF may be used in lieu of a screening ECG, provided the ECG report is made available to the investigator for assessment of study 
eligibility.
o.
A repeat FSH measurement is required at Visit 2 to confirm postmenopausal status if duration of amenorrhea is less than 12 months. Refer to Appendix 5. 
p.
At each visit during each weekly testing period, the computerized cognitive assessments with the Cogstate Brief Battery (CBB) should be administered first followed by the additional tests in 
the Cogstate Battery) before performing any other clinic procedures.
q.
At Visit 2, participants will perform the CBB: (DET, IDN, OCL, ONB) 2 times. Each set of CBB assessments should be separated by a rest period of approximately 15 minutes. Participants 
will continue with the rest of the computerized cognitive assessments on the Cogstate Battery after completing the second set of the CBB and after they are determined to be eligible based on 
the results as reported by Cogstate (see Inclusion Criterion #16).
08CSPK


PRODUCT: MK-0000  
27
PROTOCOL/AMENDMENT NO.: 413-05
MK-0000-413-05 FINAL PROTOCOL
02-DEC-2022
Single-Blind
Double-Blind
Study Period:
Screening
Placebo 
Run-In
Intervention
Post-
studya
Notes
High Frequency Testing 
Periodb
n/a
1
2
3
4
5
6
n/a
Each Testing Period 
occurs within 5 
consecutive days
Visit Numberb/Name
1c
2d
Baseline/
Familiar-
ization
3
4e
Random-
ization
5
6
7f
8
9
10g
11
12
13
14
15
16
17
18
19
20
Scheduled Week
-5
-3
-1
2
4
6
8
10
Scheduled Day (d)b
-32c
≥14 
days 
after
V1
MMSEd
-14e
Within
4d 
prior
1f
Within 
4d 
prior
15g
Within 
4d 
prior
29
Within 
4d 
prior
43
Within 
4d 
prior
57
70
All clinic procedures 
are in the morning 
(AM). Dosing in the 
evening (PM).
Within 4d priord AM
PM
AM PM
AM PM
Study Visit Window (Days)
(-30)c
±3e
+3
+3
+3
+3
r.
The LFCB assessments may be conducted over the course of more than 1 day (i.e. Visits 3-4; and Visits 18-19) to decrease participant burden (See Section 8.10.2 for details on 
recommendation for splitting the visit). The rater should ensure consistency in the administration of the LFCB during the course of the study. If the screening/pre-treatment LFCB was 
performed over 2 days for an individual participant at Visits 3-4, then the LFCB scheduled for the later timepoint (i.e.Visit 18) should also be consistently split across 2 days (i.e. Visits 18-19).
s.
For FCSRT, no other cognitive assessments can be performed during the 20-30 min interval between Trial 3 of Free and Cued Recall and the start of Delayed Recalled portion of the FCSRT. 
The participant will be given another short break during this time.
t.
For the Verbal Fluency Test, only the letter fluency and category fluency tasks will be administered.
u.
Alternately, blood for biomarkers for AD diagnosis may be collected at the next scheduled blood draw at either Visit 10 or Visit 13 (to coincide with the blood collection for the donepezil 
assay).
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2
INTRODUCTION
2.1
Study Rationale
Drug development for symptomatic therapies in AD is burdened by significant time and cost 
to assess the potential efficacy of new drugs. Proof-of-concept studies for new drugs rely on 
demonstrating improvement on clinical cognition measures such as the ADAS-Cog. 
However, many of these clinical endpoints are bound by limited sensitivity to disease 
progression and/or drug response. As a result, large sample sizes and long treatment duration 
(typically ≥ 3-6 months) are required to provide sufficient statistical power to begin to 
establish efficacy. Moreover, pathophysiological changes secondary to AD lead to cognitive 
fluctuations that create variability in patient cognitive performance and thus in assessment of 
cognition endpoints. Thus, assessment of cognitive pharmacodynamic effects using these 
standard measurements in small patient populations is not feasible.
Consequently, there is an urgent need for novel clinical trial methodology that will support 
high-predictive value decision-making in the early clinical development environment to 
trigger investment in fully-powered symptomatic trials. The rationale for this study is to 
assess whether one candidate methodology is viable. This methodology would have the 
ability to interrogate and assess probability of benefit of pro-cognitive effects of 
investigational compounds in a relatively low number of patients affected by AD pathology, 
in a relative rapid manner to improve clinical throughput, make better Phase 1 triaging 
decisions across different mechanisms, and reduce the number of low-probability of success 
compounds advanced for testing in Phase 2. 
2.2
Background
The overall objective of this study is to rigorously test a novel high-frequency “burst” testing 
paradigm designed to leverage the repeatability of computerized batteries for a precise 
assessment of cognitive capability, as a means to assess pro-cognitive pharmacodynamic 
potential in one or two key sentinel cognitive domains with strong face validity for predicting 
efficacy in more standard assessment tools. Donepezil will be used as the investigational 
agent in this study as it is the most commonly prescribed cholinesterase inhibitor prescribed 
for symptomatic treatment of AD. As such, it is anticipated that treatment effect data on 
donepezil obtained through this study can be used as benchmarking data for evaluation of 
performance of future pro-cognitive compounds being assessed using this high-frequency
testing paradigm.
2.2.1
Information on Study-Related Therapy
The most common AEs of donepezil, defined as those occurring at a frequency of at least 5% 
in patients receiving 10 mg/day and occurring at twice the rate observed in placebo treated 
participants, are largely predicted by the cholinomimetic effects of donepezil HCl. These 
include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia. These 
AEs are typically of mild intensity and transient, resolving during continued donepezil HCl 
treatment without the need for dose modification [Jackson, S., et al 2004]. Less-commonly 
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observed AEs include depression and sleep disturbances (e.g., abnormal dreams and 
somnolence).
Donepezil is ~ 96% bound to human plasma proteins, mainly to albumins (~ 75%) and alpha-
1 acid glycoprotein (about 21%) over the concentration range of 2 to 1000 ng/mL. Donepezil
is both excreted in the urine intact and extensively metabolized to four major metabolites, 
two of which are known to be active, and a number of minor metabolites, not all of which 
have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and 
undergoes glucuronidation. Donepezil has a Tmax of ~3 to 4 hours and half-life ~ 70 hours.
Refer to the approved labeling for additional detailed background information on donepezil
[U.S. Prescribing Information 2018].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in experimental medicine will directly benefit from 
participation, as these studies are designed to provide information about the safety and 
effectiveness of an investigational procedure.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The following objectives will be evaluated in participants diagnosed with mild cognitive 
impairment or mild Alzheimer’s Disease.
Objectives
Endpoints
Primary
•
To assess the ability of a repeated high-
frequency site-based computerized 
cognitive assessment to evaluate the 
potential treatment effects of donepezil 
compared with placebo in participants with 
MCI/mild AD following a limited treatment 
duration (8 weeks treatment).
Hypothesis: After 8 weeks of daily 
treatment, the change from the placebo run-
in period (Week -1) in average proportion 
of correct responses on the One Card 
Learning (OCL) task (a task of visual 
learning) in participants receiving donepezil 
compared with participants receiving 
placebo will be ≥2 percentage points. 
•
Proportion of correct responses on 
the OCL task at Weeks -1, 2, 4, 6, 
and 8
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Objectives
Endpoints
Secondary
•
To characterize the inter- and intra-subject 
variability associated with repeated high-
frequency site-based computerized 
cognitive test administration in participants 
with MCI/mild AD.
Hypothesis: The overall standard deviation 
associated with the change from the 
placebo run-in period in average OCL 
repeated measurements (arcsine square root 
transformed) after 8 weeks of donepezil 
treatment is ≤0.1.
•
Proportion of correct responses on 
the OCL task 
•
To assess the ability of a repeated high-
frequency site-based computerized 
cognitive assessment to evaluate the 
potential treatment effects of donepezil 
after 8 weeks of treatment compared to 
after the placebo run-in period in 
participants with MCI/mild AD.
Hypothesis: After 8 weeks of daily 
treatment in participants receiving 
donepezil, the proportion of correct 
responses in the OCL task will improve 
relative to performance during the placebo 
run-in period by a clinically-meaningful (>2 
percentage points) degree of change.
•
Proportion of correct responses on 
the OCL task
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Objectives
Endpoints
Tertiary/Exploratory
•
To characterize the inter- and intra-subject 
variability associated with repeated high-
frequency site-based computerized 
cognitive test administration in participants 
with MCI/mild AD. 
•
Detection (DET), Identification 
(IDN), One Back (ONB), 
International Shopping List Test 
(ISLT), Modified Groton Maze 
Learning Test (GMLTM), 
Continuous Paired Associate 
Learning (CPAL), International 
Daily Symbol Substitution Test -
Medicines (IDSSTM), 
International Shopping List Test -
Delayed Recall (ISRL) at Weeks  
-1, 2, 4, 6, and 8
•
To assess the ability of a repeated high-
frequency site-based computerized 
cognitive assessment to evaluate the 
potential treatment effects of donepezil 
after 8 weeks of treatment compared to 
after the placebo run-in period in 
participants with MCI/mild AD.
•
DET, IDN, ONB, ISLT, 
GMLTM, CPAL, IDSSTM, ISRL 
at Weeks -1, 2, 4, 6, and 8
•
To assess the ability of a repeated high-
frequency site-based computerized 
cognitive assessment to evaluate the 
potential treatment effects of donepezil 
compared with placebo on tests associated 
with cognitive domains of attention, 
executive function and verbal/ visual 
memory in participants with MCI/ mild AD 
following 8 weeks of treatment.
•
DET, IDN, ONB, ISLT, 
GMLTM, CPAL, IDSSTM, ISRL 
at Weeks -1, 2, 4, 6, and 8
•
To evaluate the psychometric properties of 
the Face-Name Associative Memory Exam
(FNAME) as a measure of learning.
•
FNAME
•
To establish the operational feasibility of 
frequent site-based administration of 
cognitive function testing in participants 
with MCI/mild AD.
•
Study Execution
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Objectives
Endpoints
•
To assess participants’ and study
partner/informants’ perception and comfort 
with the use of at-home device (e.g. 
tablet/computer) in future studies.
•
Questionnaires
•
To evaluate the differences in baseline 
cognitive performance and response to 
donepezil treatment (comparison to placebo 
and to pre-treatment baseline) between 
different participant subgroups defined by 
positive and negative results for various 
exploratory plasma biomarkers for AD 
diagnosis.

Plasma levels of beta-amyloid and 
phospho-tau isoforms
•
To assess within-subject test-retest 
reliability of various exploratory plasma 
biomarkers for AD diagnosis in replicate 
samples taken during the study.
•
Plasma levels of beta-amyloid and 
phospho-tau isoforms
•
To explore the relationship between genetic 
variation and 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.
•
Apolipoprotein E (APOE) 
genotyping
•
Germline genetic variation and 
association to clinical data 
collected in this study.
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multi-site study to evaluate the 
effects of donepezil 10 mg PO daily on cognitive function using a high-frequency site-based 
computerized cognitive assessment, the Cogstate Computerized Battery, in participants with 
MCI or mild AD.
The study will enroll approximately 36 participants randomized to receive over-encapsulated 
donepezil or placebo in a 2:1 ratio following a single blinded run-in period with placebo. No 
formal stratification is planned per site; however, an allocation schedule with separate panels 
for disease status (ie, Panel A for MCI and Panel B for mild AD) will be used with each
panel incorporating randomization in a 2:1 ratio. Efforts will be made to enroll a minimum of
12 participants meeting AD diagnostic criteria (Panel B) in this study. The number of 
participants per panel (ie, disease status) may be adjusted by the Sponsor based on 
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enrollment metrics to ensure timely study completion, but the total sample size of the study 
will remain at approximately 36. The rationale for ensuring this minimum number of 
participants meeting AD criteria is that prior data suggest a more robust treatment signal for 
OCL testing in this population, and ensuring adequate representation of mild AD in the 
overall study sample will increase probability of study success.
Potential participants will have a Screening Visit (V1) to determine if they meet inclusion 
and exclusion criteria. Following the Screening Visit, participants will have a 
Baseline/Familiarization Visit (V2), during which the Cogstate battery will be administered 
for familiarization purposes as described in Section 1.3 (SoA). Participants who met the 
selection criteria at that point will return for 2 additional visits (V3 and V4) during that week, 
when a Cogstate battery as described in Section 1.3 (SoA) will be administered to further 
acclimate them to the high-frequency testing paradigm, and to provide a standard replicate 
testing period consistent with a mock baseline assessment initiating the placebo run-in 
period.  As part of the testing during this week, participants will also undergo additional 
paper/pencil cognitive baseline (pre-treatment) assessment for the purposes of 
characterization of baseline cognitive status across several different performance domains 
before randomization into one of two treatment sequences.
After the Randomization Visit (V4), participants will enter a single-blind placebo run-in 
period of approximately 2 weeks.  During the second week of the placebo run-in period, 
participants will undergo a high-frequency testing period with a Cogstate battery as described 
in Section 1.3 (SoA). This testing period will cover 3 clinic visits (V5-7) over the span of 5 
consecutive days. Testing will be administered on-site. 
After completing the placebo run-in period, participants will enter a double-blind 
intervention period of approximately 8 weeks and initiate treatment with either over-
encapsulated donepezil or placebo. Participants allocated to donepezil will be given 
donepezil 5 mg PO daily for approximately 2 weeks (at least 14 days), followed by titration 
to donepezil 10 mg PO daily depending on tolerability. Once titrated to donepezil 10 mg PO 
daily, participants will remain on this daily dose for 6 weeks. To maintain the study blind, 
participants allocated to placebo will follow the same dose titration regimen. Participants will 
return to the clinic at two-week intervals during the treatment period, to undergo 
computerized Cogstate testing following the high-frequency schedule as described in 
Section 1.3 (SoA) (at V8-10, V11-13, V14-16, and V17-19). The paper/pencil based 
cognitive battery (which was administered at baseline prior to randomization) will be 
administered a second time at the End of Treatment Visit (V19). A Post-Study Visit (V20) 
will be conducted at least 14 days after the last dose of study drug. 
This protocol is written with flexibility to accommodate the inherent dynamic nature of 
Phase 1 clinical studies. Refer to Section 8.10.5 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.
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4.2
Scientific Rationale for Study Design
Rationale for High-Frequency Computerized Test Administration 
Over the past decade, successive external and internal studies have progressively evaluated 
the ability of repeated, high-frequency computerized cognitive testing to identify potential 
treatment effects of pro-cognitive compounds in small study populations over a limited 
treatment duration. Based on these studies, the high-frequency testing methodology is 
believed to improve measurement precision with enhanced sensitivity to detect cognitive 
change. Overall, the idea of high frequency testing is based on the premise that patients with 
AD pathology typically have significant fluctuations in cognitive performance over time, and 
even on a daily basis. As a result, solitary assessments of cognition conducted several months 
apart (as typically done with the ADAS-Cog, for example) may not accurately assess a 
patient’s true mean cognitive baseline or their true mean cognitive performance after several 
months of treatment with a symptomatic pro-cognitive compound. However, if cognitive 
testing could be conducted more frequently, individual test variability could have less impact 
on overall performance, supporting more accurate determination of true baseline cognition 
and providing more reliable results of potential treatment effect.
Previously, AstraZeneca conducted a study (CogMemo) in collaboration with Cogstate Ltd.
in patients with mild to moderate AD, in which a standardized computerized test battery 
(Cogstate) as well as a standardized paper/pencil battery (ADAS-Cog and the NTB) were 
administered to participants multiple times on a monthly basis to obtain an assessment of 
baseline cognition, followed by repeated testing around the time of efficacy at 4, 8 and 12 
weeks of treatment with donepezil. Group differences were detected after 8 and 12 weeks of 
treatment when applying individual Cogstate tests, but not using more conventional cognitive 
assessments, such as ADAS-Cog and the NTB. These results seemed to support the idea that 
providing a standard, computerized battery with multiple forms (to minimize practice and 
learning effects after repeated administration) with the potential for reduced examiner-
induced variability, could improve the ability to detect a treatment signal in a smaller 
population over a short duration of treatment.  In particular, the OCL, a measure of visual 
learning in the Cogstate Battery was able to demonstrate a statistically-significant treatment 
effect following monthly administration.
A follow-up Merck experimental medicine study (MK-0000-318) conducted in conjunction 
with Cogstate Ltd. included repeated testing of increased frequency (~ 5 in-home test
administrations over a 7-day test period, conducted at baseline and repeated monthly after 1, 
2 and 3 months of treatment) in participants with MCI and participants with mild AD treated 
with donepezil versus placebo. Cogstate tests were conducted in the presence of a trained 
testing supervisor in the participants’ homes in order to ensure a consistent test environment, 
support participant motivation, and assist with technical challenges. The primary objective of 
the study was to evaluate inter- and intra-subject variability following repeated 
administration of the Cogstate battery, particularly the OCL test. The secondary objective of 
the study was to evaluate a potential treatment effect among donepezil-treated participants, 
comparing change in performance on the OCL test after 12 weeks of treatment with OCL 
performance at baseline. The study achieved both objectives, demonstrating low inter- and 
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intra-subject variability and a relative improvement in OCL performance within donepezil-
treated participants following 12 weeks of treatment. These results further supported the idea 
that high-frequency computerized test administration improves the potential to detect a 
symptomatic pro-cognitive effect in smaller participant populations over a limited duration of 
treatment. However, there were some limitations with the study. First, while 36 total 
participants were included in the study, only a limited number of participants (N=6) were 
allocated to treatment with placebo, precluding extensive analysis of treatment effects 
between donepezil- and placebo-treated participants. Second, operational challenges of 
locating treatment-naïve participants with MCI and AD combined with difficulties with 
locating site staff willing to travel to participants’ homes and subsequent coordination of 
home supervisor/participant scheduling led to extended recruitment timelines and required 26 
months to complete the study. 
The current study will build on these prior evaluations and respond to previously- identified 
challenges. Like the CogMemo study and MK-0000-318, it will include a limited number of 
study participants in an affected patient population of participants with MCI and mild AD. 
Like the CogMemo and MK-0000-318 studies, this study will include high-frequency 
repeated administration of a computerized test battery (Cogstate). However, in contrast to 
MK-0000-318, in which supervised testing was conducted in participants’ homes, this study 
will conduct cognitive testing in the clinic. This shift is hypothesized to help standardize the 
test environment and mitigate sources of variability in at-home testing scenarios that may 
impede determination of a potential treatment effect signal. The recruitment and retention 
benefit of ensuring trained test administrators could engage participants directly in their 
homes was also not deemed sufficient rationale for continuing to pursue this approach due to 
its overall operational complexity. 
The overall study duration for an individual participant will be approximately 15-19 weeks 
from Screening to Post-Study Visit, compared with 24 weeks for MK-0000-318. 
Rationale for Study Treatment Duration
While the MK-0000-318 study evaluated the Cogstate effects of 12 weeks of treatment with 
donepezil (including 2 weeks of treatment with 5 mg PO daily, followed by 10 weeks of 
treatment with donepezil 10 mg PO daily), post-hoc analyses of donepezil treatment effect in 
the study data indicate that the earliest potential treatment effect may be seen following a 
minimum of 6 total weeks of treatment with donepezil, including 2 weeks treatment with 
donepezil 5 mg PO daily followed by titration up to 10 mg PO daily for 4 weeks. Additional 
positive treatment efficacy was observed following longer durations of donepezil treatment 
(10- and 14- weeks).This study will include an 8-week donepezil treatment duration, 
including an initial 2 weeks treatment with donepezil 5 mg PO daily followed by titration up 
to 10 mg PO daily for 6 weeks. The rationale for this treatment duration is to minimize the 
overall exposure for participants in the study, but also to ensure sufficient treatment duration 
(i.e. > 6 weeks, based on MK-0000-318 findings) to maximize probability of observing 
efficacy. 
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Rationale for Test Frequency
Subjects will participate in repeated test assessment periods approximately every two weeks 
after initiating treatment. The two-week interval was selected based on the t1/2 of donepezil, 
which is approximately 70 hours and as a result is expected to reach steady-state 
concentrations after approximately two weeks of daily dosing. Assessments conducted after 
Week 2 in the Treatment Period are expected to assess potential treatment effect once steady-
state PK is reached for donepezil 5 mg PO daily; assessments at Week 4 in the Treatment 
Period will assess potential treatment effects once steady-state PK is reached for donepezil 
10 mg PO daily; and assessments at Week 8 will assess treatment effects at a timepoint 
following the minimal treatment duration following which a treatment effect signal was 
observed in MK-0000-318.
As in MK-0000-318, participants in this study will complete multiple test administrations for 
each test period (Weeks 2, 4, 6, 8, 10). The number of repeated assessments is based on the 
minimum number of daily assessments required to ensure adequate test reliability and 
treatment effect response as estimated from the MK-0000-318 data.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no direct efficacy assessments in this study.
4.2.1.2
Safety Endpoints
Safety for all participants will be assessed throughout the study by monitoring for clinical 
AEs, including physical/neurological examinations, C-SSRS, VS, and laboratory safety tests 
(serum chemistry, hematology, and urinalysis).
4.2.1.3
Pharmacokinetic Endpoints
To enable the use of plasma concentrations to explain effects on safety and 
pharmacodynamic endpoints observed, plasma samples will be collected during the study for 
measuring donepezil concentrations as needed. 
4.2.1.4
Pharmacodynamic Endpoints
Computerized Cognitive Assessment with the Cogstate Battery
Cogstate computerized cognition testing has been developed and tested over the years as a 
standardized, easy-to-deploy solution to assess human cognitive function across various 
domains, with minimal reliance on rater training for test administration. Although 
computerized cognition testing batteries were developed for periodic usage, their high 
number of testing versions and lack of learning effects makes them ideal candidate for
evaluation in high-frequency, repetitive testing paradigms as well. This study will utilize the 
Cogstate Brief Battery (CBB), which includes the primary endpoint OCL testing, as the core 
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testing battery; this study will also evaluate other Cogstate tests in a similar high-frequency 
paradigm.
The CBB is designed to be sensitive to the various domains of cognitive impairments that 
characterize AD patients yet simple enough for individuals with cognitive impairment to 
complete without requiring great support or assistance. The specific modules for this Battery 
(DET, IDN, OCL, ONB) emphasize the assessment of attention, processing speed, episodic 
memory, and working memory, all of which are typically impaired in amnestic MCI and 
early AD. 
The OCL task has been selected as the primary endpoint for the primary and secondary 
objectives because: (1) OCL is a test of episodic memory, the primary deficit in mild AD; (2) 
OCL was the most sensitive measure to detect a treatment effect in the CogMemo and MK-
0000-318 studies; and (3) OCL was the most sensitive measure to detect cognitive decline in 
an observation study in participants with very early AD. As such, it is an ideal sentinel 
cognitive domain to interrogate for signs of relevant pharmacodynamic activity in AD 
patients.
The potential treatment effects generated on other cognitive endpoints evaluating domains of 
attention, executive function and visual/ verbal memory will be evaluated as exploratory 
endpoints in order to support future use of this platform for compounds that may have a 
different mechanism of action from donepezil. 
The additional modules aside from those included in the CBB selected for this study were 
identified in conjunction with Cogstate, to appropriately measure the cognitive domains of 
attention, executive function and verbal/ visual memory while preserving test efficiency and 
reducing test length. The combined modules (CBB + additional modules) take approximately 
30-45 minutes to complete. The selected tasks for this study are outlined in Table 1.
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Table 1
Description of Outcome Measures for the Cogstate Battery
Test Name
Main 
Cognitive 
Domain
Unit of
Measurement
Description of Outcome
Cogstate Brief Battery
Detection Task 
Psychomotor 
function 
Speed (msecs)
Speed of performance; mean of the 
log10 transformed reaction times for 
correct responses
Lower score = better performance
Identification 
Task
Attention 
Speed (msecs)
Speed of performance; mean of the 
log10 transformed reaction times for 
correct responses
Lower score = better performance
One Card 
Learning Test 
Visual 
Learning 
Accuracy (arcsin 
proportion correct)
Number of correct recognitions of 
previously seen stimuli 
One Back Test 
Working 
memory 
Accuracy (arcsin 
proportion correct)
Number of correct recognitions of 
previously seen stimuli 
Additional Testing Modules
International 
Shopping List 
Test – Learning 
Trials
Verbal 
learning
Accuracy (n 
words)
Number of words recalled 
successfully across the three learning 
trials 
International 
Shopping List 
Test – Delayed 
Recall 
Verbal 
memory 
Accuracy (n 
words)
Number of words recalled 
successfully after the delay 
Modified 
Groton Maze 
Learning Test 
Executive 
function 
Number of errors 
Number of errors made while 
learning the location of a hidden 
pathway over 5 consecutive trials
Continuous 
Paired Associate 
Learning 
Visual 
Learning 
Accuracy (n 
errors)
Number of errors made in learning 
associations between six patterns and 
six locations 
International 
Daily Symbol 
Substitution 
Test 
Complex 
Attention  
Accuracy (n 
correct)
N correct symbols placed under their 
numbers in accord with the key
Face Name 
Associative 
Memory Exam 
Learning 
Accuracy (number 
correct)
Number of correct pairings over 12 
trials
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Low Frequency Cognitive Battery
Additional paper/pencil cognitive assessments will be administered at a low frequency at 
baseline (pre-treatment) and at the end of treatment; these measures are referred to as the 
Low Frequency Cognitive Battery (LFCB) in this study. Broadly, the LFCB assesses 
executive functioning, attention, psychomotor speed and memory.  It is comprised of 
paradigms commonly used in MCI/AD clinical trials, including verbal fluency (phonemic 
and category), psychomotor speed (symbol/digit substitution), and verbal learning and 
memory (with controlled attention and processing), as well as less frequently used measures 
to further probe the domain of executive functioning. These assessments will be used to 
characterize baseline cognitive status across several different performance domains before 
participants are randomized into one of 2 treatment sequences.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug 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.
In addition to studying variation across the human genome, apolipoprotein E (APOE) 
genotyping will specifically be investigated for its potential impact on response to treatment.
4.2.1.5.2
Exploratory Plasma Diagnostic Biomarkers for Alzheimer’s Disease
The study will collect plasma for exploratory analysis of biomarkers indicating the presence 
of AD pathology (e.g. plasma beta-amyloid or plasma phospho-tau levels). These emerging 
biomarkers are not fully validated, but the rationale for inclusion of exploratory analysis in 
this study is to ascertain whether participants with biomarker data indicating the presence of 
AD pathology exhibit more robust changes in performance in OCL and other cognitive 
testing, and whether their responses to donepezil treatment are more pronounced than 
participants without biomarker evidence of AD pathology. This exploratory analysis will be 
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carried out on a post-hoc basis, using a plasma biomarker panel or panels that have not been 
specifically identified at the time of this protocol finalization, but are under investigation in 
other efforts and are anticipated to be available at the completion of this study.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
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 
FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR research are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
Placebo will be used in this study to allow for an appropriate assessment of the cognitive 
platform’s ability to detect treatment effect from donepezil 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 an 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
Donepezil is indicated for the treatment of dementia of the Alzheimer’s type. In mild-to-
moderate Alzheimer’s patients, the maximum recommended dosage of donepezil in patients 
is 10 mg per day. A daily dose of 5 mg per day is indicated as a necessary titration step 
before administration of 10 mg to minimize side effects (typically gastrointestinal-related). 
The titration period in this study is 2 weeks, which is shorter than the recommended titration 
period in the donepezil label. The rationale for this shortened duration is to minimize 
participant time-in-study, and to further minimize the duration in treatment required to 
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observe a positive pro-cognitive pharmacodynamic effect. In MK-0000-318 (filed under IND 
112,913), 30 participants with mild-to-moderate AD or MCI were titrated from 5-mg to 
10-mg donepezil over 2 weeks. Of these, 4 participants randomized to receive donepezil 
discontinued participation due to an AE. The AEs leading to discontinuation were headache, 
insomnia, dizziness, and pruritus. In no cases were these AEs directly attributable to the 
accelerated titration approach in this study based on time of onset. Of note, in the pivotal 
donepezil studies, patients were titrated from 5 mg to 10 mg on Day 8 of treatment [U.S. 
Prescribing Information 2018]. Additional internal studies have similarly found that 2-week 
titration periods for donepezil are generally well-tolerated in the mild-to-moderate AD and 
MCI populations, further indicating that the safety and tolerability risk of this accelerated 
titration approach is low. 
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Treatment-naïve male/female participants with MCI or mild AD between the ages of 55 and 
85 years (inclusive) will be enrolled in this study. Inclusion of participants above the age of 
80 years will need Sponsor’s approval before enrollment. Efforts will be made to enroll at 
least one-third of the participants meeting mild AD in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1.
Has an MMSE score between 18 and 28 (inclusive) at Screening (V1) and Baseline
(V2), as confirmed by the rater training vendor. MMSE score at Screening and Baseline 
must be within 3 points of one another.
Note: Due to the close timing between Visits 2 and 4, it is important to submit 
recordings and worksheets following the completion of the V2 MMSE to the rater 
training vendor to allow the rater training vendor to provide eligibility confirmation 
prior to completion of Visit 4. Participants whose scores are well within the specified 
range may proceed at the investigator’s discretion. Participants with borderline MMSE 
scores (including potential differences between V1 and V2 MMSE ≥3 points of one 
another) should not proceed with randomization at Visit 4 until the eligibility 
confirmation from the rater training vendor is received.
2.
Has a diagnosis of MCI or AD
a.
If the participant is diagnosed with MCI, the participant must:
1. Have a history of subjective memory decline with gradual onset and slow 
progression for at least 1 year before Screening, that is either corroborated by an 
informant who knows the participant well or is documented in medical records
2. Have a general cognitive function and activities of daily living sufficiently 
intact, based on clinical assessment, so as not to meet criteria for mild AD 
dementia based on NINCDS-ADRDA criteria
3. Have a CDR scale score of 0.5, including a memory subscale score ≥ 0.5, as 
confirmed by the investigator (NOTE: If the Global CDR is 0.5, then the CDR 
sum of boxes [CDR-SB] score must be at least 2.0)
b. If the participant is diagnosed with AD, the participant must:
1. Have a history of cognitive and functional decline with gradual onset and slow 
progression for at least 1 year before Screening, that is either corroborated by an 
informant who knows the participant well or is documented in medical records
2. Meet the criteria for a diagnosis of probable AD based on NINCDS-ADRDA 
criteria 
3. Have a CDR scale score of 1.0, as confirmed by the investigator
3.
Has an MHIS score of ≤4.
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4.
Has an MRI scan at Screening to rule out non-AD conditions contributing to cognitive 
dysfunction. A scan that has been taken within 1 year of the Screening visit may be 
used, but either the scan or the diagnostic report must be made available for the 
investigator to independently assess.
Demographics
5.
Is male or female, from 55 years to 85 years of age (inclusive), at the time of signing 
the informed consent. Inclusion of participants above the age of 80 years will need 
Sponsor’s approval before enrollment.
Female Participants
6.
A female participant is eligible to participate if: 
-
She is a WONCBP, as defined in Appendix 5.
Informed Consent
7.
The participant (or legally acceptable representative) has provided documented
informed consent/assent for the study. The participant may also provide consent/assent 
for FBR. However, the participant may participate in the study without participating in 
FBR.
Additional Categories
The participant must:
8.
Have a reliable and competent study partner/informant (e.g. spouse, family member, or 
other caregiver) who is knowledgeable of the participant’s condition and progress and 
able to read, understand, and speak the designated language at the study site. The study 
partner/informant should understand the nature of the study and assist the participant 
with adherence to study requirements (e.g., study medication, visit schedules, 
evaluations). The study partner/informant must:
a.
Be willing to provide documented informed consent,
b. Have contact with the participant at least three days a week for a minimum of six 
waking hours a week,  
c.
Be willing to accompany the participant to the Screening Visit where the CDR scale 
is administered. 
d. Be willing to participate in assessments that require study partner/informant input 
(e.g., CDR scale).
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9.
Be willing to provide a blood sample for APOE genotyping. Note: Results from the 
APOE genotyping will not be used for determining eligibility.
10.
Have results of clinical laboratory tests (hematology, chemistry, TSH, RPR, and 
urinalysis) within normal limits or clinically acceptable to the investigator at Screening.
11.
Have results of a PE within normal limits or clinically acceptable to the investigator at 
Screening.
12.
Have a history of academic achievement and/or employment sufficient to exclude 
intellectual disability as determined by the investigator.
13.
Be able to speak, read, hear, and understand the language of the study staff and the ICF, 
and possess the ability to respond verbally to questions, follow instructions, and 
participate in study assessments based on the investigator's judgment (with legal 
representative input, as applicable). 
14.
Be able and willing to adhere to the study visit schedule.
15.
Have visual acuity (with corrective lenses if needed), visual function (e.g. absence of 
color blindness), hearing (with supportive devices if needed), and gross and fine motor 
skills adequate to support study participation, based on participant’s medical history.
16.
Be capable of performing the Cogstate battery assessments, as demonstrated at the 
Baseline/Familiarization Visit (Visit 2). Results of this assessment will be reported by 
Cogstate in the form of an Inclusion Report accessible via their electronic eSource 
Platform.
Note: After battery completion, Cogstate will issue an auto-query for any test that fails 
their performance check during the screening period. The Sponsor should be consulted 
promptly if any Cogstate performance check auto-queries are issued at Visits 3 and 4. 
Participants should not be randomized at Visit 4 prior to this discussion with the 
Sponsor.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1.
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 assessment of suicidal ideation on the C-SSRS) 
in the past 5 years or suicidal behavior in their lifetime.
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2.
Has evidence of a clinically relevant neurological disorder other than AD at screening, 
including but not limited to: Parkinson's disease, frontotemporal dementia, Huntington's 
disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear 
palsy, dementia with Lewy bodies, other types of dementia, neurosyphilis or that led to 
persistent cognitive deficits, or has a history of seizures or epilepsy within the last 5 
years before screening.
3.
Has a known history of stroke that is clinically important in the investigator's opinion or 
has a diagnosis of possible, probable, or definite vascular dementia in accordance with 
the NINDS-AIREN criteria.
4.
Has history of multiple episodes of head trauma, or head trauma resulting in protracted 
loss of consciousness, or serious infectious disease affecting the brain, within the prior 
3-5 years.
5.
Has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-5, 
including schizophrenia or other psychotic disorder, bipolar disorder, major depression, 
or delirium. Note: Major depression in remission for at least 6 months prior to 
screening is not exclusionary.
6.
Has evidence of a current episode of major depression based on site investigator’s 
judgment. A score on the 15-item GDS of 5 or more requires an assessment by an 
appropriate health care professional to evaluate for the presence of major depression. 
Note: Participants with a score of 5 or more who are not diagnosed with major 
depression following such an assessment may be included in the study with Sponsor’s 
approval.
7.
Has a recent or ongoing, uncontrolled, clinically significant medical condition within 2 
months of the Screening visit (such as, but not limited to, diabetes, hypertension, 
thyroid or endocrine disease, congestive heart failure, angina, cardiac or GI disease, 
dialysis, or abnormal renal function) other than the condition being studied such that, in 
the judgment of the investigator, participation in the study would pose a significant 
medical risk to the participant. Controlled comorbid conditions (including diabetes, 
hypertension, heart disease, etc.) are not exclusionary if stable within 2 months of the 
Screening visit. All concomitant medications, supplements, or other substances should 
be kept as stable as medically possible during the study. Note: urinary tract infections 
at screening are not exclusionary if adequately treated (as documented by repeat 
urinalysis) prior to randomization.
8.
Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous 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 Screening visit).
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9.
Has a relative contraindication to donepezil including sick sinus syndrome, first, 
second, or third degree heart block, bradycardia (with heart rate < 50 bpm at screening), 
active GI bleeding, Zollinger-Ellison syndrome, uncontrolled peptic ulcer disease, or 
uncontrolled asthma.
10.
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. Exception:
Participants with selected allergies may be enrolled with Sponsor’s approval.
11.
Is positive for HBsAg, hepatitis C antibodies or HIV as confirmed by the central 
laboratory. Exception: Participants with a history of chronic hepatitis C infection with 
a documented cure and/or a positive serologic test for HCV with a negative HCV viral 
load may be included following Sponsor consultation.
12.
Has clinically significant vitamin B12 or folate deficiency in the 6 months immediately 
before screening, or vitamin B12 or folate deficiency in addition to increased serum 
homocysteine and methylmalonic acid levels at screening as determined by central 
laboratory normal values. Note: Participants may be enrolled following initiation of 
B12 therapy for at least 1 month prior to randomization and with B12 level confirmed 
to be above lower limits of normal.
13.
Has any clinically significant condition or situation, other than the condition being 
studied that, in the opinion of the investigator, would interfere with the study
evaluations or optimal participation in the study.
Prior/Concomitant Therapy
14.
Has ever received acetylcholinesterase inhibitors, memantine, or other symptomatic AD 
treatment. Exception: Inclusion of participants who last received such treatment 6 
months ago (or earlier) prior to screening may be acceptable with Sponsor’s approval.
15.
Is unable to refrain from or anticipates the use of any of the medications listed in Table 
2 throughout the duration of the study including the Poststudy visit. There may be 
certain medications that are permitted (see Exceptions noted in Table 2 and Section 
6.5).
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Table 2
Prohibited Medications that Require a Washout Period Prior to Completion of 
Visit 1 (Non-inclusive List)
Prohibited Medications,
Supplements, and other
Substances/Examples
Notes
Washout Period
Prior to Completion of 
Visit 1a
AD Medications
• Acetylcholinesterase inhibitors: 
galantamine, huperzine A, 
rivastigmine, tacrine, 
• memantine
6 months
Analgesics/Narcotics
• codeine, dextromethorphan,
hydromorphone, meperidine, 
morphine, oxycodone, pethidine 
hydrochloride, propoxyphene
(Darvon) and its variations, 
combination products that contain a 
narcotic
Exception: if dosing is ≤2 doses/week
(i.e. not regularly used) this is acceptable
Prohibited 48 hrs before study visits
30 days or 5 half-lives,
whichever is greater
Anesthetics (General)
3 months
Anticonvulsants/Mood Stabilizers
• carbamazepine, levetiracetam, 
lithium, oxcarbazepine, 
phenytoin, valproic acid
Exception: use of pregabalin and
gabapentin for neuropathic pain is 
acceptable
30 days or 5 half-lives,
whichever is greater
Antidepressants (e.g. monoamine oxidase 
inhibitors [MAO],
those with anticholinergic potency, or 
cognitive side effects: i.e. tricyclics)
• amitriptyline, amoxapine, 
clomipramine, desipramine, doxepin, 
imipramine, isocarboxazid, maprotiline, 
nortriptyline, phenelzine, protriptyline, 
tranylcypromine, trimipramine
Exception: selective serotonin reuptake 
inhibitor (SSRI) and serotonin–
norepinephrine reuptake inhibitor (SNRI) 
antidepressants are permitted. 
Trazadone 150-200 mg for sleep is 
permitted.
30 days or 5 half-lives,
whichever is greater
Antihistamines
• chlorpheniramine, clemastine, 
cyproheptadine, diphenhydramine, 
hydroxyzine, pyrilamine
Exception: non-sedating antihistamines
are allowed
30 days or 5 half-lives,
whichever is greater
Antipsychotics/Neuroleptics
• chlorpromazine, clozapine, 
fluphenazine, loxapine, 
methotrimeprazine, molindone, 
perphenazine, pimozide, promazine, 
thioridazine, thiothixene, trifluoperazine
Exception: asenapine, aripiprazole,
lurasidone, olanzapine, quetiapine, 
risperidone, ziprasidone. Must be on
stable dose 3 months prior to Screening
Visit 1. Quetiapine is contraindicated 12 
hours prior to cognitive testing.
30 days or 5 half-lives,
whichever is greater
Antivertigo
• meclizine, scopolamine
30 days or 5 half-lives,
whichever is greater
Corticosteroids
• oral, intravenous, or intramuscular
• systemic glucocorticoids 
(dexamethasone)
Exception: topical and nasal use is
acceptable
30 days or 5 half-lives,
whichever is greater
CYP3A4 inhibitors (strong)
• strong: boceprevir, clarithromycin, 
conivaptan, indinavir, itraconazole, 
ketoconazole, lopinavir/ ritonavir, 
mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole
• other: grapefruit juice
Exception: topical use of these, if
indicated, is acceptable
30 days or 5 half-lives,
whichever is greater
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Prohibited Medications,
Supplements, and other
Substances/Examples
Notes
Washout Period
Prior to Completion of 
Visit 1a
CYP3A4 inducers (strong)
• strong: avasimibe, barbiturates, 
carbamazepine, nevirapine, phenytoin, 
pioglitazone, primidone, rifabutin, 
rifapentine, St. John’s Wort (hypericum)
• systemic glucocorticoids 
(dexamethasone)
Exception: inhaled steroids are permitted
30 days or 5 half-lives,
whichever is greater
Gastrointestinal
• Antidiarrheal: diphenoxylate w/atropine
• Antispasmodics: belladonna, clidinium, 
chlordiazepoxide, dicyclomine, 
hyoscyamine,
propantheline, trimethobenzamide
• Antiulcer: cimetidine, ranitidine
30 days or 5 half-lives,
whichever is greater
Selected Herbal Supplements/Vitamins
• Gingko biloba, ginseng, Huperzia 
serrata (Qian Ceng Ta), kava-kava, S-
Adenosyl methionine (SAMe), 
tryptophan, valerian
Exception: Melatonin, Vitamin E, and 
Vitamin B12 are permitted.
Consult Sponsor if questions on other
herbal supplements/vitamins
30 days or 5 half-lives,
whichever is greater
Hypnotics/Sedatives/ Benzodiazepines
• chlordiazepoxide, clonazepam, 
diazepam, flurazepam, meprobamate, 
triazolam
Exception: Regular use (up to 3 times per 
week) of the following medications for sleep
is acceptable if stable for at least 3 months 
prior to Screening Visit: trazodone, 
mirtazapine, zaleplon ≤ 5mg,
zopiclone/eszopiclone ≤ 5 mg, zolpidem ≤
5 mg, or lorazepam ≤ 1.0 mg.  However 
these medications may not be used for 24
hours before a cognitive assessment. More 
frequent use may be allowed upon 
agreement from the site and Sponsor. For 
countries where these medications are not 
available, alternatives will be designated by 
the Sponsor
30 days or 5 half-lives,
whichever is greater
Investigational Compounds
30 days or 5 half-lives,
whichever is greater
Muscle Relaxants
• cyclobenzaprine, dantrolene, 
methocarbamol, orphenadrine
30 days or 5 half-lives,
whichever is greater
Ophthalmic
• atropine
30 days or 5 half-lives,
whichever is greater
Parkinsonism
• amantadine, benztropine, biperiden, 
bromocriptine, levodopa, pergolide, 
rasagiline, selegiline, l-
deprenyl/selegiline, trihexyphenidyl
Exception: pramipexole, ropinirole, and
levodopa are allowed for treating restless leg
syndrome
3 months
Stimulant medications
• amphetamine, methylphenidate, 
atomoxetine, modafinil
30 days or 5 half-lives,
whichever is greater
a Washout should occur for 5 half-lives or the minimum specified period whichever is longer to systemically eliminate 
the medication. It is recommended that sites that pre-screen potential participants review washout requirements in 
advance. Visit 1 maybe split to accommodate an extended washout period of 30 days; refer to Section 8.10.1 for 
details.
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Prior/Concurrent Clinical Study Experience
16.
Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the Screening Visit. The window will be derived from the 
date of the last visit in the previous study.
Diagnostic Assessments
17.
Has a known history of structural changes on screening MRI scan that are clinically 
important in the investigator’s opinion, including signs indicative of vascular dementia, 
large infarct, lacunes in critical areas, space-occupying lesions, or extensive white 
matter disease.
Other Exclusions
18.
Is unwilling or not eligible to undergo an MRI scan (if a prior MRI scan is not 
available).
19.
Is under the age of legal consent.
20.
Is pregnant, is attempting to become pregnant, or is nursing children.
21.
Has a history of alcoholism or drug dependency/abuse within the last 5 years prior to 
the Screening visit.
22.
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.
23.
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.
24.
Is a regular user of cannabis, any illicit drugs or has a history of drug (including 
alcohol) abuse within approximately 5 years. Participants must have a negative UDS 
prior to randomization. Note: A participant who is a recreational user of cannabis or 
other drugs within the past 2 years can be enrolled as long as recreational use does not 
meet the definition of drug abuse and participant agrees to refrain from substance use 
for duration of study participation.
25.
Had major surgery (e.g. abdominal, thoracic, cardiac or orthopedic surgery, or any 
procedure requiring general anesthesia) within 3 months prior to the Screening visit that 
in the opinion of the investigator would interfere in the participant’s ability to fully 
participate in the study.
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26.
Has undergone neuropsychological testing (including the MMSE) or cognitive 
remediation in the past 4 weeks.
27.
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.
28.
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain their usual diet. Participants should 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 until the poststudy visit.
Fasting requirements for study procedures are limited to laboratory safety evaluations as
specified in Appendix 2. Participants will fast from all food and drinks, except water, for at 
least 8 hours prior to the Screening and Poststudy visits.
Participants may administer trial medication with or without food, but trial medication should
be taken with ~240 ml (8 oz) of water.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants should refrain from consumption of caffeinated beverages or xanthine-
containing products from 12 hours before the Screening and Poststudy visits.
Caffeinated beverages or xanthine-containing products should be limited to no more than 
6 units per day (1 unit = 120 mg of caffeine). It is recommended that participants consume no 
more than their usual amounts of caffeine on the days of cognitive assessments, refrain from 
caffeine for at least 1 hour prior to the start of the Cogstate cognitive battery assessment and 
continue to refrain from caffeine until the completion of all cognitive assessments.
5.3.2.2
Alcohol Restrictions
Participants should refrain from consumption of alcohol 24 hours before the Screening and 
Poststudy visits. Participants should also refrain from consumption of alcohol for 12 hours
before each clinic visit when cognitive assessments will be performed.
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At all other times, alcohol consumption should be limited to no more than 1 alcoholic 
beverage 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
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) as defined by the CRU.
During the study, if the participant is a smoker, he/she should limit the number of cigarettes 
to 10 per day. Participants should not smoke within 30 minutes before the start of the 
Cogstate cognitive battery assessment.
5.3.3
Activity Restrictions
Participants should avoid unaccustomed strenuous physical activity (ie, weightlifting, 
running, bicycling, etc.) from the Screening visit until administration of the initial dose of 
study drug, throughout the study and until the Post Study visit.
Participants who are provided non-pharmacological treatments, such as day care, may 
continue these throughout the study. The frequency should not change unless medically 
indicated.
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 does not titrate successfully, 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.
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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 (over-encapsulated donepezil and matching placebo) will be packaged to 
support enrollment and replacement participants as required. When a replacement participant 
is required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Active
Experimental
Donepezil 
hydrochloride
Drug
Capsule
5 mg
5 mg, 10 
mg
Oral
QD dosing
Experimental
IMP
Provided 
centrally by 
Sponsor
Placebo
Placebo 
Comparator
Placebo
Drug
Capsule
0 mg
N/A
Oral
QD dosing
Placebo
IMP
Provided 
centrally by 
Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
In this protocol, the donepezil hydrochloride is over-encapsulated to match the placebo in order to maintain study blind.
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All supplies indicated in Table 3 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 to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation schedule is shown in Table 4.
Table 4
Sample Allocation Schedule
Sample Size (N)
Run-In Period
Intervention Period
A (MCI)
16
Placebo 
Donepezil 
A (MCI)
8
Placebo 
Placebo
B (Mild AD)
8
Placebo 
Donepezil 
B (Mild AD)
4
Placebo 
Placebo
AD=Alzheimer’s disease; MCI=mild cognitive impairment
The suggested sample size per treatment sequences and panel maybe adjusted by the sponsor based on enrollment metrics 
to ensure timely study completion. The allocation schedule will include additional allocation numbers per panel to enable 
flexibility to enroll more MCI (n >24) or more mild AD (n >12) participants as determined by the sponsor, but the total 
sample size of the study will remain approximately 36 participants. Participants may be replaced as needed to ensure that 
approximately 36 evaluable participants complete the study as described in Section 9.9.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Disease status (MCI vs mild AD) as defined by CDR score at Screening
6.3.3
Blinding
During the placebo run-in period, a single-blinding technique will be used. The participant 
and his/her study partner will not know the study intervention they are administered; 
however, the investigator and Sponsor personnel or delegate(s) who are involved in study 
intervention administration or clinical evaluation of the participants will be aware of the 
intervention assignments to placebo. The placebo used during this period will be packaged 
identically to the drug supplies used in the subsequent treatment period during which a
double-blinding technique with in-house blinding will be used. The donepezil is over-
encapsulated to mimic the appearance of the placebo so that the blind is maintained. The 
participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the 
study intervention administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
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See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
•
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each subsequent visit. Compliance will be assessed by 
direct questioning and site review of the completed study intervention dosing diary as 
captured by the participant/study partner. In addition, compliance will be monitored via 
counting of returned capsules at selected site visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the eCRF.
•
A record of the number of donepezil/placebo capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or 
dose reductions will also be recorded in the eCRF.
•
When participants are dosed at the site (for those who are domiciling overnight, as per 
Section 8.1.18), they will receive study intervention directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the 
clinic will also be recorded in the study intervention dosing diary (source documents).
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study or during time periods specified by this protocol for that medication (Table 2
in Section 5.2). If there is a clinical indication for any medications specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
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Table 2 outlines specific restrictions for concomitant therapy during the course of the study; 
some exceptions are noted. For any concomitant medication not listed, the sponsor should be 
consulted. When medically possible, doses of concomitant medication, including medical 
food, should remain stable throughout the entire study.
In the event that a participant requires an extended washout period (ie, greater than 2 weeks) 
to accommodate discontinuation of a prohibited medication(s) or other therapy, an 
abbreviated Visit 1 may be performed (see Section 8.10.1). After the participant has 
completed the proper washout based on Table 2, the participant will return to complete the 
remaining Visit 1 procedures/assessments. Once the participant has fully completed Visit 1 
and eligibility has been confirmed, the participant may proceed to Visit 2 per protocol.
Potential participants should not be withdrawn from medically necessary medications in 
order to participate in the study, but rather, these patients should be excluded from the study, 
due to their medical condition and the requirement for these therapies.
Paracetamol/acetaminophen or low dose non-steroidal anti-inflammatory drugs 
(ibuprofen/naproxen) may be used for minor ailments without prior consultation with the 
Sponsor.
In addition, the following concomitant medications/vaccinations are permitted:
1. All participants: Any immunizations/vaccinations
All participants: Any medication, excluding those listed in Table 2, intended for treatment of 
chronic, stable medical conditions (e.g. hypertension, vascular disease, diabetes), if 
participant has maintained compliance with a stable dosing regimen for at least 3 months 
prior to randomization
2. Female participants: hormonal replacement therapy is allowed, if on a stable dose 
initiated at least 3 months prior to randomization
3. All participants: AD medical foods/supplements (e.g., Axona®, Souvenaid®) is allowed 
if participant has been on a stable dosing regimen for at least three months prior to 
screening and plans to remain on the same regimen during the trial (unless a medically 
necessary change is needed)
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
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The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification/Titration
During the double-blind intervention period, following 14 days of dosing, the dose of study 
medication will be increased from 5 mg donepezil (or placebo) to 10 mg donepezil (or 
placebo) at Visit 10. The decision to increase the dose will be made by the investigator based 
on his/her assessment of the participant’s ability to tolerate the dose titration. If, in the 
opinion of the investigator, the participant is not suitable for dose titration, the sponsor 
should be consulted to determine the next step.
If the participant (or study partner on behalf of the participant) reports an initial tolerability 
issue after the dose titration step at Visit 10, the investigator will determine the participant’s 
treatment plan and next steps (ie  down-titrate to the original dose of 5 mg QD, continue with 
10 mg QD (if applicable), or discontinue study intervention), with the decision to be mutually 
agreed upon by the investigator, the sponsor, and the study participant. For participants that 
were maintained at 5 mg donepezil (or placebo) due to tolerability issues, re-challenge to 10 
mg may occur prior to Visit 13. However, participants who fail the mandatory first titration 
at 2 weeks of treatment will be excluded from the final primary analysis and may be 
replaced, at the discretion of the sponsor. However, data from participants failing the 
mandatory dose titration will be collected and may be included in additional post-hoc or 
exploratory analyses.
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 for 
the double-blind intervention period of this study]. 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.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or 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 3 consecutive 
days within the double-blinded period or has 8 cumulative missed doses over the double-
blinded period.
•
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.
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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed approximately 151 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
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The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Documented informed consent from each participant’s study partner/informant (referred to as 
study partner informed consent) will also be obtained by the investigator or qualified 
designee.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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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 30 days before starting the study.
When pre-screening potential participants, it is recommended that the site review the 
washout requirements of prohibited medications (Table 2) in order to allow sufficient time
for washout prior to completion of Visit 1. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
As noted in Section 1.3, the treatment/randomization number is assigned to a participant at 
Visit 4 once it has been confirmed that the participant meets all eligibility criteria. To prepare 
for Visit 4, the site staff will contact the Sponsor for a treatment/randomization number to be 
used for this upcoming visit. Refer to the study operations manual for detailed procedures for 
requesting a treatment/randomization number.
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8.1.8
Study Intervention Administration
Administration of study intervention will occur at home (or in-clinic if the participants are 
kept domiciled overnight for selected days) as described in Section 1.3 Schedule of 
Activities.
Participants will receive one bottle of study intervention at the Randomization Visit (V4) and 
at every two weeks at the third clinic visit for each testing period. Prior to dispensing a new 
bottle of study intervention, the previous bottle that was dispensed will be collected. Each 
bottle will contain enough study intervention to cover the duration of approximately 2 weeks 
(when the third clinic visit is scheduled within the permissible window per Section 1.3).
Each bottle dispensed at V4 will contain the placebo (matched to the over-encapsulated 
donepezil 5mg). Each bottle dispensed at V7 and thereafter will contain either the over-
encapsulated donepezil 5 mg or placebo (matched to the over-encapsulated donepezil 5 mg). 
Participants will be instructed on how to administer study intervention by the site staff. Study 
intervention should begin on the evening of the visit when medication is dispensed.
While taking the study intervention at home, participants who vomit after dosing or miss a
dose should be instructed to continue with the next scheduled dose.
8.1.8.1
Timing of Dose Administration
All study medication will be administered orally with water in the evening prior to retiring. 
Study intervention can be taken with or without food. 
All doses should be taken at approximately the same time each night. Participants/study
partners will record time of dosing in a study drug dosing diary. On days when study 
intervention is administered in-clinic at selected site(s), dose administration will be witnessed 
by the investigator and/or study staff.
If, in the opinion of the investigator, the timing of dose administration should be adjusted for 
an individual participant based on the participant’s ability to tolerate the dose, the Sponsor 
Clinical Director must be consulted to determine next steps. In some cases, changes in timing 
of daily dosing may be permitted following Sponsor consultation.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.4.1 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-
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up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for 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
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.
In the event that 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.
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Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Rater Expectations and Training for Clinical and Cognitive Assessments
For this study, raters of clinical and/or cognitive assessments (MHIS [Section 8.13], MMSE
[Section 8.1.14], CDR [Section 8.1.15], GDS [Section 8.1.16], C-SSRS [Section 8.3.6], Low 
Frequency Cognitive Battery [Sections 8.7.2, 8.7.3, and 8.7.4], Cogstate Battery [Section 
8.7.1]) will be pre-qualified based on education and prior experience conducting protocol-
specific or similar assessments, and experience working with patients with AD, MCI, or 
similar populations. Raters will undergo the applicable training and/or certification prior to 
conducting assessments in the study. Further, rater performance on some of these 
assessments will be carefully evaluated and monitored to ensure and maintain adequate 
reliability throughout the study. It is recommended that the same rater conducts the same 
assessment(s) throughout the study for a given participant and/or study partner, where 
feasible.  Details will be specified in the MOA and in training materials provided by the rater 
training vendor or by Cogstate Ltd. 
To ensure the continued quality of the assessments (MMSE, CDR, and other cognitive 
measures that constitute the Low Frequency Cognitive Battery), raters will be asked to audio
record assessments at study visits. Some or all of these recordings will be reviewed by the 
rater training vendor, and raters will be provided feedback on the quality of their
performance in order to help ensure data integrity.  Based on this feedback, raters may be 
asked to consider changing their initially recorded scores if errors are identified. Routine 
rater meetings may be conducted to assess and maintain reliability for the duration of the 
study. Raters who do not perform adequately may be required to undergo additional 
remediation or may be replaced.
Recorded interviews will be secured using state of the art methods to ensure privacy. 
Recordings will only be reviewed by the rater training vendor for quality control purposes 
and will be destroyed in accordance with current retention requirements, unless local 
regulatory authorities or IRBs/ERCs have different requirements for storage.
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8.1.13
Modified Hachinski Ischemia Scale 
The MHIS, a tool to identify the possibility of a vascular etiology for the participant’s 
cognitive impairment, will be completed by a qualified, trained rater. Additional detailed 
information concerning administration, scoring and documentation may also be provided by 
the rater training vendor and in the MOA.
8.1.14
Mini Mental State Examination 
The paper version of the MMSE, a brief measure of cognition, will be administered to the 
participant and scored and recorded by a qualified, trained rater. Additional detailed 
information concerning administration, scoring and documentation may also be provided by 
the rater training vendor and in the MOA.
8.1.15
Clinical Dementia Rating Scale
The CDR, an assessment of global functioning, including performance in activities of daily 
living and cognition, will be administered to both the participant and the participant’s study
partner/informant and scored and recorded by a qualified, trained rater. Additional detailed 
information concerning administration, scoring and documentation may also be provided by 
the rater training vendor and in the MOA.
8.1.16
Geriatric Depression Scale  – 15 Item
The 15-item GDS, a depression screening tool, will be administered to the participant and 
scored by a qualified, trained rater. Additional detailed information concerning 
administration, scoring and documentation may also be provided by the rater training vendor
and in the MOA.
8.1.17
Magnetic Resonance Imaging
MRI scans should be performed during the screening period after all other inclusion and 
exclusion criteria has been met at Visit 1. Previous scans performed within 1 year of the 
documented ICF may be used in lieu of a screening scan provided the scans themselves or 
the report of the scan are made available to the investigator for review. The results of the 
MRI scan must be available, prior to Visit 2, to evaluate for study eligibility.
8.1.18
Domiciling (Optional)
For sites that have domiciling capability to keep participants overnight, the site may offer 
study participants the option to stay in the unit for the duration of the testing period in order 
to reduce the transportation burden associated with the high frequency clinic visits. The study
partner is not required to stay overnight but may do so if requested by the study participant 
and the site can accommodate. If the participant is staying overnight at the CRU, then the 3 
testing days should occur on consecutive days. At the discretion of the investigator, 
participants will report to the CRU the evening before the first scheduled testing day of each 
testing period and remain in the CRU until after the completion of study procedures on the 
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third testing day. Participants may be permitted to leave the unit, for emergency situations 
only, during the 3-day domiciling period at the discretion of the investigator after discussion 
with the Sponsor. 
Study staff will also witness and administer the study medication and work with the 
participants in completing the dosing diary on the nights when the participants are in the 
CRU.
8.1.19
Participant and Study Partner Questionnaires (Optional)
At selected study visits as outlined in Section 1.3 SoA, the study participant and/or study
partner will each complete a survey regarding their experience with the computerized
cognitive battery testing and perspective on doing such assessments at home in a future 
clinical study.
8.1.20
History of Neuropsychological Assessments
The investigator or qualified designee will obtain a history of any neuropsychological testing 
that was performed within the past 6 months prior to Screening Visit 1 for each potential 
participant. Neuropsychological assessments include both paper/pencil cognitive measures as 
well as computerized cognitive batteries. The data to be recorded will include the name (and 
version, if known) of the individual measure or battery and the date when the assessment was 
performed. This historical information may support the characterization of the study 
population and the interpretation of the data from the cognitive assessments performed in this 
trial.
8.2
Efficacy Assessments
There are no direct efficacy assessments in this study. 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from Screening to Poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) 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.
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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 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Neurological Examination
Targeted neurological examination will be conducted according to the procedures outlined in 
Appendix 9.
8.3.3
Vital Signs
8.3.3.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate, Respiratory Rate, and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semi-recumbent 
position for at least 10 minutes prior to having VS measurements obtained. Semi-recumbent 
VS will include HR, systolic and diastolic BP, respiratory rate and body temperature at 
timepoints indicated in the SoA. The correct size of the BP cuff and the correct positioning 
on the participants' arm is essential to increase the accuracy of BP measurements.
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.
8.3.4
Electrocardiograms
Single 12-lead ECG will be obtained during the screening period and reviewed by an 
investigator or medically qualified designee (consistent with local requirements) as outlined 
in the SoA using an ECG machine that automatically calculates the HR and measures PR, 
QRS, QT, and QTc intervals. A previous ECG performed within 3 months of the documented 
ICF may be used in lieu of a screening ECG provided the report is made available to the 
investigator for review. 
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent position for at least 10 minutes before 
the ECG measurement.
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The correction formula to be used for QTc is Fridericia.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, 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 
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assessor should also inquire and document if this is also present at the time of the screening 
visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). Subsequent to that evaluation, only those participants whose suicidal ideation is 
considered by the evaluator to be passive, and who expressly deny any intent to act, and who, 
after evaluation, are not judged to be at serious risk for self-harm during the course of the 
study may continue in the study; other participants must be discontinued from study 
participation and receive appropriate clinical follow-up care to ensure their safety. In 
addition, all AEs of suicidal ideation or behavior must be recorded as an ECI (See 
Section 8.4.7). Sites are to designate which health care professionals are to be responsible for 
acute care on-site and to specify referral center(s) to be used for further evaluation.
8.3.7
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption or rash occurrence in determining etiology and drug relationship.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
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.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator 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, or a procedure.
From the time of intervention 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 5.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-specified 
Follow-up Period
Time Frame to Report 
Event and Follow-up 
Information to Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to outcome)
Within 24 hours of 
learning of event
Pregnancy
/Lactation Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in) 
Report all
Previously reported – Follow 
to completion/termination; 
report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar days 
of learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar days 
of learning of event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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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
Although pregnancy and infant exposure during breastfeeding are not considered AEs and 
the study population includes WONCBP, if a pregnancy were to occur during the study 
(spontaneously reported to the investigator or their designee), it is reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable
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8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT 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, suicidal behavior 
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
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 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.
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8.6.1
Blood Collection for Plasma Donepezil
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.7
Pharmacodynamics
8.7.1
Computerized Cognitive Assessments
The Cogstate battery consists of the following tests presented to the participant in the order 
listed below. Details on how each test is performed will be provided in the Cogstate 
operation manual. All Cogstate Battery measures will be administered to participants by 
qualified, trained raters according to instructions and training provided by Cogstate Ltd.
Raters should observe participants during the entire Cogstate Battery testing session and 
record notes as appropriate as the participant proceeds from one test to another. This will 
assist with addressing any Cogstate auto-queries that may arise after full battery completion.
The Cogstate Brief Battery 
The CBB measures 4 core cognitive domains and consists of 4 modules:

Detection Task (DET)- assesses psychomotor function and processing speed with a 
simple reaction time paradigm

Identification Task (IDN)- assesses attention with a forced-choice reaction time paradigm

One-Card Learning Test (OCL)- uses a pattern separation paradigm to assess visual 
memory

One Back Test (ONB)- an n-back paradigm, where n = 1, is used to measure working 
memory
Additional Testing Modules 
In addition to the Cognitive Brief Battery, the following tests from the Cogstate testing 
platform will be administered to explore the cognitive domains of complex attention, 
executive function, verbal/visual memory, and learning.  

The International Shopping List Test (ISLT [and ISRL])- uses a list-learning paradigm 
with a delayed recall component (ISRL) to assess verbal learning and memory. The 
participant will be asked to recall the words from the list approximately 15-20 minutes 
later (ISRL)

The Modified Groton Maze Learning Test (GMLTM)- employs a maze-learning 
paradigm to assess executive functioning. The participants in this trial will be 
administered a modified version of the GMLT that is more appropriate for this trial
population.
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
The Continuous Paired Associate Learning Test (CPAL)- uses a paired-associates 
learning paradigm to measure visual learning and memory.

The International Daily Symbol Substitution Test- Medicines (IDSSTM)- uses a symbol 
substitution paradigm to assess psychomotor processing speed.

The Face Name Associative Memory Exam (FNAME) - employs a face/name associates 
learning paradigm to assess visual learning and memory.
8.7.2
Free and Cued Selective Reminding Test (FCSRT)
The FCSRT is a learning and memory measure in which participants are given categorical 
cues during acquisition to help maximize semantic encoding specificity and learning.  As 
such, any deficits on recall are thought to reflect hippocampal-related memory impairment 
rather than inattention or other factors that may interfere with processing.  In this study, both 
immediate and delayed recall will be evaluated. A brief paper/pencil task, it will be 
administered to the participant and scored by a qualified, trained rater according to 
instructions from the test manual and in the Manual of Assessments (MOA).  Additional 
detailed information concerning administration, scoring and documentation may also be 
provided by the rater training vendor.
8.7.3
Wechsler Adult Intelligence Scale (WAIS-IV)-Coding
The Coding subtest of the WAIS-IV is a brief paper/pencil task assessing attention, 
psychomotor speed and visuomotor coordination.  Coding will be administered to the 
participant and scored by a qualified, trained rater according to instructions from the test 
manual and in the MOA.  Additional detailed information concerning administration, scoring 
and documentation may also be provided by the rater training vendor.
8.7.4
Tests from the Delis-Kaplan Executive Function System (D-KEFS)
Verbal Fluency 
This protocol will include two tasks of the Verbal Fluency subtest.  Letter Fluency measures 
phonemic fluency, while Category Fluency assesses semantic fluency and processing.  Both 
are considered to be executive functioning tasks involving initiation, self-monitoring and 
processing speed. Also, both are brief paper/pencil measures that will be administered to the 
participant and scored by a qualified, trained rater according to instructions from the test 
manual and in the MOA.  Additional detailed information concerning administration, scoring 
and documentation may also be provided by the rater training vendor.
Sorting 
This task is comprised of two conditions, including Free Sorting and Sort Recognition.  
Taken together, they target a variety of executive functions, including problem-solving, 
concept formation, mental flexibility, creativity, and perseveration.  A brief paper/pencil task, 
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it will be administered to the participant and scored by a qualified, trained rater according to 
instructions from the test manual and in the MOA.  Additional detailed information 
concerning administration, scoring and documentation may also be provided by the rater 
training vendor.
Twenty Questions
Also an executive functioning measure, this test assesses problem-solving, abstraction, 
categorization, and incorporation of feedback.  This brief paper/pencil measure that will be 
administered to the participant and scored by a qualified, trained rater according to 
instructions from the test manual and in the MOA.  Additional detailed information 
concerning administration, scoring and documentation may also be provided by the rater 
training vendor.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis 
•
Blood for APOE Genotyping

Blood for Exploratory Plasma Biomarkers for AD Diagnosis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for APOE genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to APOE genotypes. Leftover extracted DNA will be stored for FBR if the 
participant provides documented informed consent for FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.8.2
Exploratory Plasma Biomarkers for Alzheimer’s Disease Diagnosis Sample 
Collection
Sample collection, storage, and shipment instructions for exploratory plasma biomarker 
samples will be provided in the operations/laboratory manual.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA from Genetic Analysis and APOE Genotyping for future research
•
Leftover main study plasma from donepezil PK stored for future research 
•
Leftover main study plasma from exploratory plasma biomarkers for AD diagnosis stored 
for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
There are a total of 6 testing periods, each consisted of 3 clinic visits. It is recommended that 
the site schedules all study visits in advance when a participant is deemed eligible based on 
Visit 1 results. The 3 visits for each testing period (including the first testing cluster prior to 
Randomization) must be scheduled together, with the first 2 visits scheduled within 5 days of 
the last testing visit in that week. For example, Visits 2 and 3 are anchored by the date when 
Visit 4 is scheduled; they must be scheduled on any one of the 4 days prior to Visit 4 
Randomization. Similarly, Visits 5 and 6 are anchored by the date when Visit 7 is scheduled; 
they must be scheduled on any one of the 4 days prior to Visit 7. Preferably, each cluster of 3 
clinic visits should be scheduled within a single working week (which could include the 
following [not preceding] Saturday, if the clinic is open and staffed appropriately.) 
An example would be as follows: a potential participant has completed screening at Visit 1 
and is deemed eligible to move forward to Visit 2. The site would schedule this participant 
for Visit 2 at least 2 weeks from Visit 1, while ensuring that Visits 3 and 4 would occur 
within 4 days after Visit 2. At this time, the site would also schedule this participant for 
Visits 7, 10, 13, 16, and 19 (taken into account the permissible window for these “anchor” 
visits), while ensuring that Visits 5, 6, 8, 9, 11, 12, 14, 15, 17, and 18 will occur within the 4 
days prior to the corresponding “anchor” visit.
Study Partner Participation
The study partner/informant is required to accompany the participant to the Screening Visit, 
in order to sign the study partner informed consent and to participate in the CDR assessment. 
The study partner is not required to accompany the participant to any other study visits, but if 
he/she is not able to do so, he/she should discuss alternative arrangements with the site (eg, 
participant transportation, return of study medication and dosing diary) and availability of the 
study partner to provide input by phone as needed (eg questions related to dosing information 
captured on dosing diary, optional questionnaire related to remote testing).
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Every effort should be made to maintain the same study partner for the duration of the study. 
However, if the study partner is unable to continue with the study requirements, the study
partner should discuss with the site whether a suitable replacement can be found. If a new
study partner is identified, the new study partner will need to sign the study partner informed 
consent.
8.10.1
Screening (Visits 1-4)
The screening period ranges from approximately 3-7 weeks, including the initial testing 
period (Visits 2-4) occurring during the last week prior to randomization.
Screening Visit 1
Approximately 3-7 weeks prior to Visit 4 (when intervention allocation/randomization will 
occur), potential participants will be evaluated to determine that they fulfill the entry 
requirements as set forth in Section 5. Screening Visit 1 should occur approximately 2 weeks 
prior to Visit 2 (Baseline/Familiarization Visit) but can be initiated earlier as permitted by the 
study visit window.
If a site wishes to split the Screening Visit 1 for a participant, the site may do so for the 
following reasons:
•
Visit 1 may be split to decrease the burden of the participant/study partner due to the 
length of the visit. 
•
Visit 1 may be split in the event that a participant requires an extended washout period 
(ie, greater than 2 weeks) for prohibited medication(s) or other therapy, in accordance 
with Table 2; this is to help avoid the necessity to repeat any prior Visit 1 procedures 
assessed at the initial Visit 1.
If the site chooses to split Visit 1 for either of the reasons noted above, the site should ensure 
the comfort of study participants when considering the chronological order of procedures to 
be administered across the split screening visits. The site should also ensure that all 
prohibited medication(s) have been washed out as required per protocol prior to conducting 
the clinical and cognitive assessments (MMSE, CDR, MHIS, GDS, and C-SSRS).
The following is a recommendation of what procedures (non-inclusive) and the order they 
should be conducted at the initial portion of Visit 1: 
•
Obtain informed consent (Participant, Study Partner)
•
Review medical history
•
Preliminary review of inclusion/exclusion criteria
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•
Review of prior and concomitant medications
•
Assignment of participant’s screening number
The final portion of Visit 1 may include:
•
All clinical and cognitive assessments (MMSE, CDR, MHIS, GDS, and C-SSRS)
•
PE (including height/weight) and Neuro Exam
•
Vitals, ECG, Labs
•
MRI
The final portion of Visit 1 should be conducted preferably within 2 days of the initial
portion of Visit 1, if splitting due to visit length. Participants required to washout of a 
prohibited medication will return to complete the final Visit 1 procedures once the washout 
has been completed. The local MRI screen (if a prior one is not available for review within 
12 months prior to screening) should be the last procedure to be performed.
Assessments that are to be reviewed by the rater training vendor, such as the MMSE and 
CDR, should be sent to the vendor as soon as possible (i.e., same day that the assessment 
was performed) so specific eligibility criteria can be determined and the results can be sent 
back to the site in a timely manner. While quality review is conducted by the vendor for the
MMSE and CDR, the MMSE inclusion criteria certificate is required as documentation for 
the site to confirm participant eligibility for Inclusion Criteria 1. At Visit 1, the MMSE and 
CDR should be considered as a bundle of screening assessments that should be administered 
at the same visit (i.e. sites should not administer MMSE without administering the CDR [or 
vice versa]). If MMSE and CDR were administered, then the audio-recordings and 
worksheets will need to be submitted to the rater training vendor regardless of scoring results 
or participant eligibility status. The sponsor/rater training vendor will query the site for 
missing audio-recording/worksheets should the vendor receive one measure but not the other.
Once a participant completes Visit 1 in its entirety and continues to meet eligibility, he/she 
may proceed to Visit 2 which should occur at least 2 weeks later. Participants with positive 
UDS due to prohibited medication(s) at Visit 1 must repeat the UDS. The repeat UDS may 
be performed at Visit 2 if needed, but the repeat UDS must be negative prior to V4 
Randomization. 
Participants may be rescreened after consultation with the Sponsor. Rescreening will be 
handled on a case-by-case basis and should include all screening procedures listed in the 
SoA, including consent review. Rescreen procedures cannot be conducted within the 4-day 
period prior to intervention allocation/randomization at Visit 4.
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Baseline/Familiarization Visit and Testing Period 1 (Visits 2-4)
At least 2 weeks following Screening Visit 1, participants who have met the selection criteria 
thus far, will return to the CRU to undergo procedures to confirm eligibility at the 
Baseline/Familiarization Visit (Visit 2). This will be the first of 3 cognitive testing days for 
the first testing period in this study. This first testing period is to familiarize the participants 
with the Cogstate battery as well as the high frequency testing schedule, and to ensure 
potential participants are able to complete the computerized cognitive assessments. 
At this visit, the CBB (which consists of the DET, IDN, OCL, ONB subtests) will be 
administered 2 times separated by a rest period of approximately 15 minutes.
During this first testing period and throughout the study, participants will report to the CRU 
at approximately the same time in the morning (+/- 2 hours) for each testing visit. Cogstate 
assessments should be performed before any other procedures planned for a study visit (See 
Section 1.3 for a list of procedures). See Table 6 in Section 8.10.2 for recommended timings 
with built-in testing breaks on the longer testing visits.
Participants who have met all selection criteria at Randomization Visit 4 will be assigned 
randomization numbers and dispensed medication to take home, with instructions to take the 
first dose later that evening before retiring for bed. Study intervention dosing diary will be 
given to the participant with instructions to record dosing information nightly.
8.10.2
Treatment Period (Visits 5-19)
The treatment period consists of a single-blind placebo run-in (Visits 5-7), followed by a 
double-blind intervention period (Visits 8-19). Participants/study partners should not be 
informed of when they are transitioning into a different study period (e.g. run-in vs double-
blind intervention). 
Placebo Run In: Testing Period 2 (Visits 5-7)
After completion of Testing Period 1 (at Visit 4), randomized participants will enter the 
placebo run-in period of approximately 14 days. Participants will return to the CRU at 
approximately 2 weeks after the first testing period for Testing Period 2 consisting of 3 clinic 
visits as outlined in Section 1.3. At the third testing visit of this testing period, participants 
will return their medication bottles (containing placebo). At the end of this visit, the 
participants will be sent home with new medication bottles (containing randomized treatment 
of donepezil or placebo) with instructions to take the first dose later that evening and 
continue taking one capsule nightly. Participants will be instructed to record dosing 
information in the dosing diary.
Double-Blind Intervention: Testing Periods 3, 4, 5, and 6 (Visits 8-19)
After completion of Testing Period 2 (in the morning of Visit 7), participants will enter the 
Double-Blind Intervention period of approximately 8 weeks (with the commencement of 
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dosing later that same evening). Because participants will be dosed with donepezil 5 mg (or 
placebo) during the first 2 weeks of this intervention period before titrating up to 10 mg (or 
placebo), it is important that the third testing visit of Testing Period 3 (Visit 10) does not 
occur earlier than Day 15 when participants will exchange for new medication bottles with 
new instructions to take 2 capsules nightly for the remainder of the study. 
After completion of Visit 10 and for the remaining 6 weeks of this double-blind treatment 
period, participants will return to the CRU at approximately 2-week intervals for 3 additional 
testing periods (Testing Periods 4, 5, and 6, consisting of 3 visits each) as outlined in Section 
1.3 SoA. At the third visit of each testing period, participants will continue to exchange their 
medication bottle for a new bottle, with the exception of Visit 19 which is the End of 
Treatment visit. Participants should bring their study drug dosing diary when return to the 
clinic for medication compliance checks.
During the placebo run-in and double-blind intervention periods, participants will report to 
the CRU at approximately the same time in the morning (+/- 2 hours) for each testing visit, 
consistent with the schedule set forth during the first testing period. Cogstate assessments 
should be performed before any other procedures planned for a study visit (See Section 1.3 
for a list of procedures).
Cognitive assessments should be done in a secluded room/area, free from distractions. The 
rater should see to the participant’s needs, such as drink or restroom, prior to starting as to 
minimize interruptions. Breaks are allowed but should be appropriate and not excessive. 
Table 6 provides a sketch of the procedures and recommended timings for a participant on 
the longer testing visits at Visit 3 (Pre-Treatment) and at Visit 18 (End of Treatment). 
Table 6
Recommended Order and Timing of Procedures at Visits 3 and 18
Procedure
V3
V18
Assess concomitant medication use and AE(s)
X
X
Cogstate Battery 
X
X
15-min Breaka
X
X
FCSRTb
X
X
WAIS-IV Coding
X
X
Sorting (D-KEFS)
X
X
15-min Breaka
X
X
Verbal Fluency Test (D-KEFS)c
X
X
Twenty Questions (D-KEFS)
X
X
AE=adverse event; D-KEFS = Delis-Kaplan Executive Function System; FCSRT = Free and Cued Selective 
Reminding Test; WAIS = Wechsler Adult Intelligence Scale
a Short break to stretch or visit restroom facility; participant should not be given reading materials or 
become engrossed in other activities during this time.
b   No other cognitive assessments can be performed during the 20-30 min interval between Trial 3 of Free 
and Cued Recall and the start of Delayed Recalled portion of the FCSRT. The participant will be given 
another short break during this time.
c For the Verbal Fluency Test, only the letter fluency and category fluency tasks will be administered.
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Note that the LFCB assessments may be split across 2 days (i.e. Visits 3-4; and Visits 18-19) 
to decrease participant burden. The rater should ensure consistency in the administration of 
the LFCB during the course of the study. If the screening/pre-treatment LFCB was performed 
over 2 days for an individual participant at Visits 3-4, then the LFCB scheduled for the later 
timepoint (i.e. Visit 18) should also be consistently split across 2 days (i.e. Visits 18-19).
Table 7 is a recommendation of how the LFCB assessments should be conducted across 2 
study visits.
Table 7
Recommended Order and Timing of Procedures at Visits 3-4 and 18-19 if 
Splitting Visits
Visit 3 Split Visita
Visit 18 Split Visita
Procedure
V3
V4
V18
V19
Assess concomitant medication use and AE(s)b
X
X
X
X
Review Study Intervention Dosing Diary
X
X
Cogstate Battery 
X
X
X
X
15-min Breakc
X
X
X
X
FCSRTd
X
X
WAIS-IV Coding
X
X
Sorting (D-KEFS)
X
X
Verbal Fluency Test (D-KEFS)e
X
X
Twenty Questions (D-KEFS)
X
X
Blood Collectionsf
X
X
AE=adverse event; D-KEFS = Delis-Kaplan Executive Function System; FCSRT = Free and Cued Selective 
Reminding Test; WAIS = Wechsler Adult Intelligence Scale
a Procedures for Visit 3 and Visit 18 split across 2 days, with some procedures conducted at Visit 4 and Visit 
19, respectively.
b Includes C-SSRS (at selected timepoints per Section 1.3 SoA)
c Short break to stretch or visit restroom facility; participant should not be given reading materials or become
engrossed in other activities during this time.
d No other cognitive assessments can be performed during the 20-30 min interval between Trial 3 of Free and 
Cued Recall and the start of Delayed Recalled portion of the FCSRT. The participant will be given another 
short break during this time.
e For the Verbal Fluency Test, only the letter fluency and category fluency tasks will be administered.
f Blood for Genotyping/PK/Biomarkers (if applicable as per Section 1.3 SoA)
8.10.3
Poststudy (Visit 20)
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.
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8.10.4
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the computerized cognitive assessment with the CBB is the critical procedure
and should be administered at close to the exact time point as possible, at approximately 2-
week intervals as outlined in Section 1.3. The scheduling of the visits for the third testing 
period (Visits 8-10) must coincide with the schedule for the planned up-titration when new 
medication is dispensed with new dosing instruction (at Visit 10).
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 Collections as outlined in Table 8
Table 8
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
Visits 10, 13, 19
(per Section 1.3 SoA)
Within the 4 days prior to the scheduled visit
(to coincide with one of the testing days)
8.10.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This protocol is written with some flexibility to accommodate the inherent dynamic nature of 
Phase 1 clinical studies. Modifications to the 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.
If it is determined that incomplete or aberrant data has been captured during the CBB
assessments at any study visit, the participant may be asked to repeat the assessment. The 
evaluation to determine whether the assessment is to be repeated will be done on an 
individual basis per participant, and the decision will be reached by mutual agreement of the 
Sponsor and investigator. 
Up to additional 50 mL of blood may be drawn for safety analyses. The total blood volume 
withdrawn from any single participant will not exceed the maximum allowable volume 
during his/her participation in the entire study (Appendix 8).
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The timing of procedures for assessment of safety procedures (eg, vital signs, 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
The statistical analysis of the data obtained from this study will be conducted by the
Experimental Medicine Statistics Department in collaboration with the Translational 
Medicine Departments of the Sponsor. If, after the study has begun, changes are made to the
statistical analysis plan stated below, then these deviations to the plan will be listed, along 
with an explanation as to why they occurred, in the Results Memo for this study.
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this study. Full detail is 
in the Statistical Methods (Section 9.6).
To assess the primary hypothesis, the repeated measurements associated with proportion of 
correct response in the OCL task at each of Weeks -1, 2, 4, 6 and 8 will be averaged by each 
participant. Intermittent missing repeated measures within a time point (e.g., Week 2) will 
not be imputed and data will be averaged as available. Observations with integrity failures 
will be excluded from analysis and will not be imputed. Change from placebo run-in period
(i.e. Week -1) in the average correct response of OCL measurements will be estimated using 
a linear mixed effects model containing fixed effects for Week, proportion of correct 
response in the OCL measurement at baseline (placebo run-in period), Treatment
(donepezil/placebo) and Week by Treatment interaction with an unstructured covariance 
matrix which will account for missing data under a missing at random assumption. Least 
square variances will be estimated for change from placebo run-in period by treatment group
(donepezil/placebo) and Week 8 using above mentioned linear mixed models. The posterior 
distribution of the variances will be estimated by generating 10,000 independent draws from 
non-informative Inverse Gamma prior for both treatment groups. Conditioned on each 
variance, difference of average correct response rate of OCL task from placebo run-in period
will be generated from a Normal distribution with mean equal to the estimated least square 
mean estimate for both groups at Week 8. The posterior probability of true mean difference
between donepezil and placebo group at Week 8 relative to Week -1 is greater than 2
percentage points will be derived from the posterior distribution. A posterior probability that 
is > 55% will satisfy the primary hypothesis. 
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Power: The probability to satisfy the primary hypothesis under varying true mean change in 
donepezil population is shown in Table 9. With 36 participants (24 in donepezil and 12 in 
placebo), there is ~ 64% power to satisfy the criteria (posterior probability >55%) for the 
primary hypothesis if the true mean change from placebo run-in period is 3 percent points for 
donepezil group, assuming there no change in placebo group. For the donepezil group, if the 
true mean change is 4 percentage points then the corresponding power increases to 78%.
Table 9
Power Primary Hypothesis
True Mean Change 
in Donepezil
Prob (Post prob. of difference of true mean change from placebo run-
in between the donepezil and placebo groups
> 0.02) >
P = 60%
P = 55%
P = 50%
2.0%
0.407
0.456
0.509
2.5%
0.483
0.532
0.582
3.0%
0.576
0.635
0.684
3.5%
0.669
0.713
0.754
4.0%
0.741
0.778
0.816
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the
Experimental Medicine Statistics department of the Sponsor.
9.3
Hypotheses/Estimation
Primary: 
After 8 weeks of daily treatment, the change from placebo run-in period (Week -1) in 
average proportion of correct responses in the One Card Learning (OCL) task (a task of 
visual learning) in participants receiving donepezil compared with participants receiving 
placebo  will be ≥2 percentage points.
Secondary: 

The overall standard deviation associated with the change from placebo run-in period in 
average OCL repeated measurements (arcsine square root transformed) after 8 weeks of 
donepezil treatment is ≤0.1. 

After 8 weeks of daily treatment in subjects receiving donepezil, the proportion of correct 
responses in the OCL task will improve relative to performance on the placebo run-in 
period by a clinically meaningful (>2 percentage points) degree of change.
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9.4
Analysis Endpoints
Primary Endpoint: 
Proportion of correct responses in the One Card Learning (OCL) task (a task of visual 
learning) at Weeks -1, 2, 4, 6 and 8. 
Exploratory Endpoints:

Other measures of Cogstate test battery (Detection (DET), Identification (IDN), One 
Back (ONB), International Shopping List Test (ISLT), Modified Groton Maze Learning 
Test (GMLTM), Continuous Paired Associate Learning (CPAL), International Daily 
Symbol Substitution Test -Medicines (IDSSTM), International Shopping List Test -
Delayed Recall (ISRL)) at Weeks -1, 2, 4, 6 and 8.

Measures related to the Face-Name Associative Memory Exam (FNAME).

Measures related to Free and Cued Selective Reminding Test at Weeks -3 and 8.

Measures related to Wechsler Adult Intelligence Scale (WAIS-IV) Coding at Weeks -3 
and 8.

Measures related of D-KEFS (Sorting, Verbal Fluency, Category Fluency, Twenty 
Questions) at Weeks -3 and 8.

Measures related to beta-amyloid and phosphor-tau proteins.

Measures related to PK data. 

Measures that capture the concept of operational feasibility of frequent site-based 
administration of cognitive function testing in participants with MCI/mild AD.

Measures participants’ and study partner/informants’ perception and comfort with the use 
of at-home device (e.g. tablet/computer) in future studies.
9.5
Analysis Populations
The Full Analysis Set for each endpoint will be comprised of all participants who receive 
study medication and yield at least one valid measurement for that endpoint. Data from 
participants who discontinue donepezil therapy will be considered missing at time points 
after therapy discontinuation. 
9.6
Statistical Methods
The primary hypothesis is related to proportion of correct response in the OCL task 
associated with change from placebo run-in period (Week -1) at Week 8 for donepezil group 
compared with placebo group. To assess the primary hypothesis, the repeated measurements 
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associated with proportion of correct response in the OCL task at each of Weeks -1, 2, 4, 6 
and 8 will be averaged by each participant. Intermittent missing repeated measures within a 
time point (e.g., Week 2) will not be imputed and data will be averaged as available. 
Observations with integrity failures will be excluded from analysis and will not be imputed. 
The amount and patterns of missing data will be summarized. Change from placebo run-in 
period in the average correct response of OCL measurements will be estimated using a linear 
mixed effects model containing fixed effects for Week, proportion of correct response in the 
OCL measurement at baseline (placebo run-in period), Treatment (donepezil/placebo) and 
Week by Treatment interaction with an unstructured covariance matrix which will account 
for missing data under a missing at random assumption. Least square variances will be
estimated for change from placebo run-in period by treatment group (donepezil/placebo) and 
Week 8 using above mentioned linear mixed models. The posterior distribution of the 
variances will be estimated by generating 10,000 independent draws from non-informative 
Inverse Gamma prior for both treatment groups. Conditioned on each variance, difference of
average correct response rate of OCL task from placebo run-in period will be generated from 
a Normal distribution with mean equal to the estimated least square mean estimate for both 
groups at Week 8. The posterior probability of true mean difference between donepezil and 
placebo group at Week 8 relative to Week -1 is greater than 2 percentage points will be 
derived from the posterior distribution. We can rewrite the model as following
A posterior probability that is > 55% will satisfy the primary hypothesis. 
To assess the secondary hypothesis related to the true standard deviation (SD) associated 
with the change from placebo run-in period in average OCL measurements, the individual 
OCL measurements will first be transformed using the arcsine square root function. For each 
patient, the 3 transformed OCL measurements at each of Weeks -1, 2, 4, 6 and 8, will be 
averaged. Intermittent missing repeated measures within a time point (e.g., Week 2) will not 
be imputed and data will be averaged as available. The amount and patterns of missing data
will be summarized. The variance/covariance matrix of the average transformed OCL
measurements will be estimated using a linear mixed effects model containing fixed effects
for Week, Treatment (donepezil/placebo) and Week by Treatment interaction. An 
unstructured covariance matrix will be estimated that principally accounts for missing data 
under missing at random assumption. The Kenward & Roger’s approximation will be used to 
compute the appropriate model-based degrees of freedom. Utilizing a non-informative prior, 
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the posterior distribution of the true variance/covariance matrix will be estimated by 
generating 5000 independent draws from an inverse Wishart distribution, with the model 
based degrees of freedom and matrix S, where S is the model-based degrees of freedom times 
the model estimated variance/covariance matrix. For each generated true variance/covariance 
matrix, a plausible true SD of the change from baseline in average OCL measurements at 
Week 8 relative to Week -1 will be calculated. The posterior probability that the true SD of 
the change from baseline in average OCL measurements at Week 8 relative to Week -1 is ≤ 
0.1 will be derived from the posterior distribution. A posterior probability that is > 70% will 
satisfy the secondary hypothesis. 
To assess the secondary hypothesis related to the effect of donepezil, least square variance
will be estimated for change from placebo run-in period at Week 8 for donepezil group using 
above mentioned linear mixed models. The posterior distribution of the variance will be 
estimated by generating 10,000 independent draws from non-informative Inverse Gamma 
prior. That is, conditioned on variance, difference of average correct response rate of OCL 
task from placebo run-in period will be generated from a Normal distribution with mean 
equal to the estimated least square mean estimate for donepezil group at Week 8. The 
posterior probability that the true mean difference is greater than 2 percentage points will be 
summarized.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
Since there is only one primary hypothesis, no multiplicity adjustment will be employed.
9.9
Sample Size and Power Calculations
The probability to satisfy the primary hypothesis under varying true mean change in 
donepezil population is shown in Table 10. There are 24 participants in the donepezil group 
and 12 participants in the placebo group. In the placebo group, true mean change from 
placebo run-in period is assumed to be zero with SD of 0.06.  In the donepezil group, the SD 
of the change from placebo run-in is 0.07. SD in both groups are consistent with estimated 
SD from MK-0000-318 study. With 36 participants (24 in donepezil and 12 in placebo), there 
is ~ 64% power to satisfy the primary hypothesis if the true mean change from placebo run-in 
period is 3 percentage points for donepezil group, assuming there no change in placebo 
group. For donepezil group, if the true mean change is 4 percentage points then the 
corresponding power increases to 78% as displayed in the last row of Table 10.
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Table 10
Power associated with Primary Hypothesis 
True Mean 
Change in 
Donepezil
Prob (Post prob. of difference of true mean change from placebo run-in 
between the donepezil and placebo groups > 0.02) >
P = 60%
P = 55%
P = 50%
2.0%
0.407
0.456
0.509
2.5%
0.483
0.532
0.582
3.0%
0.576
0.635
0.684
3.5%
0.669
0.713
0.754
4.0%
0.741
0.778
0.816
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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 LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked 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.
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10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with 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 Harmonisation 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.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 11 will be performed by the central laboratory.
•
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 11
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
elevated above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting)
Calcium
Alkaline phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines) 
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody, RPR) 
•
Vitamin B12, Folate (Homocysteine and MMA are required in case of Vitamin B12 
and/or folate deficiency)
•
TSH (and T3/T4, if TSH is abnormal)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; MMA=Methylmalonic Acid; RBC=red 
blood cell; RPR=Rapid Plasma Reagin; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; TSH=Thyroid Stimulating Hormone; ULN=upper limit of normal; WONCBP=women of nonchildbearing 
potential
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent 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.”
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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:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a 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.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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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.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

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.
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(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 
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ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the 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.
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
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).
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
- Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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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.
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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.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at 
a study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated 
in the SoA. If delayed, present consent at next possible Participant Visit. Consent 
forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be 
captured in the eCRFs. Any specimens for which such an informed consent cannot 
be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected 
for future biomedical research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. 
In fact, little or no research can be conducted without connecting the clinical study data 
to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
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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.
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 
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answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
particular study, the study site will ship directly to the Sponsor-designated 
biorepository. The specimens will be stored under strict supervision in a limited access 
facility which operates to assure the integrity of the specimens. Specimens will be 
destroyed according 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.
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12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13.
References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Blood Volume Table
Screen-
ing
Random-
ization 
(Visit 4)
Treatment 
Period
(Visits 10, 13, 
19)
Poststudy
(Visit 20)
Total 
Collections
mL Per 
Collection
Total 
mL/
Test
Chemistry (including 
TSH, Vitamin B12, & 
FSH at Screening)
1
1
2
8
16
Hematology
1
1
2
3
6
Folate, MMA, RPR
1
1
8
8
Homocysteine
1
1
3
3
HIV/Hepatitis Screen  
1
1
6
6
Blood for Plasma 
Donepezil Assay
3
3
3
9
Blood for Exploratory 
Plasma Biomarkers 
for AD Diagnosis
1
1
2
20
40
Blood for APOE 
genotyping
1
1
4
4
Blood for Planned 
Genetic Analysis 
1
1
8.5
8.5
Total Blood Volume for Participant
100.5
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary (including the need for a repeat FSH to 
confirm postmenopausal status if duration of amenorrhea is less than 12 months), additional blood (up to 50 mL) may be 
obtained.
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10.9
Appendix 9: Targeted Neurological Examination
Note to the investigator: If abnormalities are observed in the Targeted Neurological Exams, 
the Investigator should do additional examinations as needed based on his or her medical 
judgment to determine participant eligibility in the study.
MODULE 1 – MENTAL STATUS EXAMINATION
(Note this module is covered by MMSE) 
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 - COORDINATION AND GAIT
D. Gait
1.
Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AD
Alzheimer’s Disease
ADAS-Cog
Alzheimer's Disease Assessment Scale-Cognitive Subscale
AE
adverse event 
APOE
Apolipoprotein E
AR
adverse reaction
BMI
body mass index
BP
blood pressure
CBB
Cogstate Brief Battery
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating- Sum of Boxes
CG
Cockcroft-Gault
CL
clearance
CNS
central nervous system 
CPAL
Continuous Paired Associate Learning (Cogstate Test)
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
D-KEFS
Delis-Kaplan Executive Function System
DET
Detection (Cogstate Test)
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 
EMA
European Medicines Agency
FBR
Future Biomedical Research
FCSRT
Free and Cued Selective Reminding Test
FDAAA
Food and Drug Administration Amendments Act
FNAME
Face Name Associative Memory Exam
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GDS
Geriatric Depression Scale
GI
gastrointestinal
GMLTM
Modified Groton Maze Learning Test (Cogstate Test)
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ID
Identification
IDN
Identification (Cogstate Test)
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Abbreviation
Expanded Term
IDSSTM
International Daily Symbol Substitution Test- Medicines (Cogstate Test)
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
ISLT
International Shopping List Test (Cogstate Test)
ISRL
International Shopping List Test – Delayed Recall (Cogstate Test)
MedDRA
Medical Dictionary for Regulatory Activities
MCI
Mild cognitive impairment
MHIS
Modified Hachinski Ischemia Scale
MMSE
Mini Mental State Examination
MOA
Manual of Assessments
MRI
magnetic resonance imaging
mRNA
messenger RNA
NDA
New Drug Application 
NINCDS-ADRDA
National Institute of Neurological and Communicative Diseases and 
Stroke/Alzheimer’s Disease and Related Disorders Association
NINDS-AIREN
National Institute of Neurological Disorders and the Stroke Association 
Internationale pour la Recherche l’Enseignement en Neurosciences
NTB
Neuropsychological Test Battery
OCL
One-Card Learning (Cogstate Test)
ONB
One Back (Cogstate Test)
OTC
over-the-counter
PCL
protocol clarification letter
PE
physical examination
PK
pharmacokinetic
po
orally
PP
per-protocol
qd
Once per day
RNA
ribonucleic acid
RPR
rapid plasma reagin
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
Tmax
Time to maximum plasma concentration
t1/2
half life
TSH
thyroid stimulating hormone
UDS
urine drug screen
V 
volume of distribution
VS
vital sign
WAIS
Wechsler Adult Intelligence Scale
WBC
white blood cell
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11
REFERENCES
[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]
[U.S. Prescribing 
Information 2018]
U.S. Prescribing Information: ARICEPT 
(donepezil hydrochloride) tablets, for oral 
use; ARICEPT ODT (donepezil 
hydrochloride) orally disintegrating tablets: 
Dec 2018.
[05L9XJ]
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