Clinical trial NCT02660983
Conditions: Dementia Associated With Cerebrovascular Disease
Sponsor: Eisai Co., Ltd.
Start date: 2013-08-05; Completion date: 2018-12-21
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives are to confirm that donepezil hydrochloride has superior efficacy compared with placebo in improving cognitive function, as measured by Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), and to demonstrate that donepezil hydrochloride has superior efficacy compared with placebo in improving global function, as measured by Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus), in patients with dementia associated with cerebrovascular disease (VaD).

Detailed description:
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study with an open-label extension. The study consists of 3 phases; screening phase (1 to 4 weeks), double-blind phase (24 weeks), and Open-label extension phase (24 weeks). Participants, who have completed the double-blind phase and want to continue the study participation, can be enrolled in the 24-week open-label extension phase.

Arms: arm 1: Participants will receive donepezil matching placebo, once daily in the evening during the double blind period. arm 2: Participants will receive donepezil 5 milligram (mg), once daily in the evening during the titration phase and then the dose will be increased to 10 mg at Week 4 during the double blind period. During the maintenance period, dose reduction to 5 mg/day will be permitted only when 10 mg/day is intolerable due to adverse events. arm 3: All participants who will complete the double-blind phase and want to continue the study participation, can be enrolled in the 24-week open-label extension phase. In this phase, treatment will be initiated at 5 mg/day, and the dose will be maintained until Week 6 (Day 28-42). After assessing clinical response during the period by examination, the dose can be increased to 10 mg/day. Dose reduction (from 10 mg/day to 5 mg/day) will be permitted when the investigator judges it difficult to continue the 10 mg/day administration. It will be possible to increase the dose to 10 mg/day again.
Interventions: intervention 1: Donepezil hydrochloride intervention 2: Donepezil matching placebo intervention 3: Donepezil hydrochloride
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2020-K082-418
Study Protocol 
Title:
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study of Donepezil Hydrochloride (E2020) in Patients 
with Dementia Associated with Cerebrovascular Disease
Representative 
Sponsor:
Eisai Co., Ltd.
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112-8088, Japan
(Local license holder: Daewoong Co., Ltd., 163-3 Samseong-dong, 
Gangnam-gu, Seoul)
Investigational 
Product Name:
E2020/Aricept (donepezil hydrochloride)
Indication:
Dementia Associated with Cerebrovascular disease
Phase:
Phase 4
Approval Date:
V1.0
V2.2
19 June 2012 (original protocol)
6 July 2017
GCP Statement:
This study is to be performed in full compliance with International 
Conference on 
Harmonisation 
of 
Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) and regulations. All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential. It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or 
performing this study.


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Co-sponsor
No.
Company
1
Korean Drug Co., Ltd.
2
Dong-A Pharmaceutical Co., Ltd.
3
Myungmoon Pharm. Co., Ltd.
4
Myung-In Pharmaceutical Co., Ltd.
5
Samjinpharmaceutical Co., Ltd.
6
CJ CheilJedang Corporation
7
SK Chemicals Co., Ltd.
8
Youngjin Pharm. Co., Ltd.
9
Yuhan Corporation
10
Ildong Pharmaceutical Co., Ltd.
11
JW Pharmaceutical Corporation
12
Jeil Pharmaceutical Co., Ltd.
13
Chong Kun Dang Pharmaceutical Corp.
14
Korea Pharma Co., Ltd.
15
Hanmi Pharmaceutical Co., Ltd.
16
Whanin Pharmaceutical Co., Ltd.
17
Hanlim Pharm. Co., Ltd.
18
Reyon Pharmaceutical Co., Ltd.
19
Hyundai Pharm Co., Ltd.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.
E2020
Name of Active Ingredient
Donepezil hydrochloride
Study Protocol Title
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of 
Donepezil Hydrochloride (E2020) in patients with Dementia Associated with Cerebrovascular 
Disease
Investigator(s)
TBD
Site(s)
Approximately 25 centers in Korea
Study Period and Phase of Development
From June 2013 to January 2019, Phase 4
Objectives
Co-Primary objectives
• To confirm that donepezil hydrochloride (E2020) has superior efficacy compared with 
placebo in improving cognitive function, as measured by Alzheimer’s Disease Assessment 
Scale-Cognitive subscale (ADAS-cog), in patients with dementia associated with 
cerebrovascular disease (VaD).
• To demonstrate that donepezil hydrochloride (E2020) has superior efficacy compared with 
placebo in improving global function, as measured by Clinician’s Interview-Based 
Impression of Change-plus Caregiver Input (CIBIC-plus), in patients with VaD.
Secondary objectives
• To evaluate the efficacy (as measured by MMSE and executive function test) and safety 
of E2020 compared with placebo, in patients with VaD.
Study Design
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study with 
an open-label extension. The main part of the study consists of 2 phase; screening phase (SCR; 
1 to 4 weeks), and double-blind phase (DB; 24 weeks, placebo-controlled). DB phase includes 
2 periods; titration and maintenance. The duration of titration period is 4 weeks.
Prior to performing any procedures or evaluation, written informed consent will be obtained. 
Up to 4 weeks prior to randomization, prospective patients will be screened to confirm their 
diagnosis and suitability for study entry. Subjects who continue to meet all of the inclusion 
and none of the exclusion criteria will be randomly assigned to receive either donepezil or 
placebo. Donepezil or placebo will be taken once daily in the evening for the duration of their 
participation in the study.


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Donepezil 5 mg will be administered in the titration period and then the dose will be increased 
to 10 mg at Week 4 (Day 28-35) according to investigator's clinical judgment. During the 
maintenance period, dose reduction to 5 mg/day will be permitted only when 10 mg/day is 
intolerable due to adverse events. In this case, the dose cannot be escalated up to 10 mg/day 
again.
(Open-label Extension)
Subjects, who have completed the DB phase and have consented to continue participation of 
the study, can be enrolled in the 24-week open-label extension phase. In this phase, treatment 
will be initiated at 5 mg/day, and the dose is maintained until Week 6 (Day 28-42). After 
assessing clinical response by examination, the dose can be increased to 10 mg/day. Dose 
reduction (from 10 mg/day to 5 mg/day) will be permitted when the investigator judges it 
difficult to continue the 10 mg/day administration. It is possible to increase the dose to 10
mg/day again. Subjects will visit the study institution at Week 6, 12, and 24.
Number of Subjects
Total 324 subjects will be randomized (162 subjects/group)
Inclusion Criteria
Patients who meet all of the following criteria will be eligible for inclusion in the study:
1. Male or female, age ≥40 years at the time of informed consent.
2. Possible or probable dementia associated with cerebrovascular disease as defined by 
NINDS-AIREN Criteria with dementia of greater than 3 months duration.
3. Radiological evidence of cerebrovascular disease.
4. Mini-Mental State Examination (MMSE) score is ≥ 10 and ≤ 24 at both Screening and 
Baseline. 


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5. Clinical Dementia Rating (CDR) ≥ 1.
6. Outpatients who are physically healthy, and ambulatory or ambulatory-aided (i.e., walker, 
cane or wheelchair). 
7. Written informed consent (IC) is obtained from the patient (if possible) and from the 
patient’s legal guardian prior to being exposed to any study-related procedures. Even if 
unable to provide written IC, the patient must assent verbally to participating in the study 
and the record should note this assent. The caregiver must separately provide IC for his/her 
own participation in the study.
8. Patients having caregivers who submit written consent to cooperate with this study, have 
regular contact with the patient (i.e., an average of ≥ 4 hours/day and ≥ 3 days/week), 
provide patients’ information necessary for this study, ensure the regular administration of 
assigned donepezil, as well as all concomitant therapies, at the correct dose, and escort the 
patients on required visits to study institution.  
If, during the study, the designated caregiver relinquishes his/her responsibilities to 
another caregiver, the new caregiver must provide IC, and otherwise similarly qualify for 
inclusion in the study. If no replacement caregiver is available who meets the caregiver 
criteria, the subject must be discontinued from this study. 
9. Patients who can visit study institution as required following with investigator’s 
instruction.
10. Patients who have vision, hearing, speech, motor function and comprehension sufficient to 
be able to comply with testing procedures (glasses, contact lens, and hearing aid 
permissible).
11. Patients who meet prohibition/restriction of using concomitant medications before 
Screening.
12. Comorbid medical conditions are clinically stable prior to Baseline, unless otherwise  
specified. The following situations should be given particular attention;
                 a. Patients with risk factors of hypertension and cardiac disease may be enrolled, 
provided that hypertension is well controlled by medication (supine diastolic blood 
pressure < 95 mmHg) and cardiac disease (e.g. angina pectoris, congestive heart 
failure, or right bundle branch block) is stable on appropriate medication for at 
least 12 weeks prior to Screening. Peripheral vascular disease must have been 
stable for 12 weeks prior to Screening. No elective surgical procedures should be 
planned during the course of the study (e.g., vascular bypass procedures or 
coronary artery bypass surgery).
b. Patients with diabetes mellitus or risk factors for diabetes mellitus may be enrolled, 
provided that the patient’s disease is stable and that there have been no recent 
(within 12 weeks of Screening) hospitalizations for diabetic ketoacidosis, 
hyperosmolar coma, or hyperglycemia. Patients with non-insulin-dependent 
diabetes may be enrolled if controlled on diet or oral medications. All diabetic 
patients must have a HbA1c concentration of ≤ 10% and a random serum glucose 


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concentration of ≤ 250 mg/dL at Screening.
               c. Patients with risk factors of stroke may be enrolled, provided that the disease 
process has been stable or controlled on medication for greater than 12 weeks prior 
to Screening. Patients receiving anticoagulation with warfarin are eligible for 
inclusion in the study if the International Normalized Ratio (INR) for prothrombin 
time is within the therapeutic range for prophylaxis (1.4-3.0) and the dose of 
warfarin is stable. Patients with prosthetic heart valves, who require full 
anticoagulation, should have a stable (≥ 3 months) INR in the range of 2.5-3.5.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded:
1. Anti-dementia drug therapy (cholinesterase inhibitors or memantine) within 12 weeks 
prior to Screening.
2. Clinical and/or radiological evidence for other serious degenerative neurological disorders 
or neuropsychiatric disorders.
e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, 
Creutzfeldt-Jacob disease, dementia with Lewy Bodies, normal pressure 
hydrocephalus, olivopontocerebellar atrophy, multiple system atrophy, brain 
tumor, progressive supranuclear palsy, idiopathic seizure disorder, subdural
hematoma, multiple sclerosis, active cerebral vasculitis, schizophrenia, and 
bipolar or unipolar depression
3. Known human immunodeficiency virus disease, neurosyphilis, or a history of significant 
head trauma followed by persistent neurological deficits or known structural brain 
abnormalities.
4. Hypothyroidism at Screening.
Patients may be enrolled, provided that they are on a stable dose of medication for at last 
12weeks prior to Screening, have normal thyroid stimulating hormone and free thyroxine at 
Screening, and are considered euthyroid. 
5. Vitamin B12 or folate deficiency at Screening. 
Patients who are currently receiving B12 supplementation by oral or parenteral injection may be 
included, provided that dosing regimen has not changed for 12 weeks, plasma B12 levels are 
normal or above normal and there is documented evidence of continued cognitive deterioration 
after initiation of B12 treatment.
6. Evidence of a new TIA or stroke that occurs within 12 weeks prior to Screening, even if 
the symptoms are minor and do not require hospitalization, are excluded.
These patients may subsequently become eligible for inclusion, if no new stroke or TIA is noted 
for 12 weeks (3 months) and all other criteria are met.  
7. Supine diastolic blood pressure ≥95 mmHg at Screening or Baseline.  
8. Complication of sick sinus syndrome, abnormal auricular and atrioventricular junction 
conductions (AV block, ≥ II ventricular block, etc.), or with a prolonged QT/QTc interval 


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(> 450 ms) as demonstrated by a repeated ECG.
9. A history of life-threatening arrhythmias (e.g., unstable atrial flutter, unstable atrial 
fibrillation, ventricular tachycardia, ventricular fibrillation, or torsade de pointes).
10. Evidence of clinically significant, severe, active, or unstable gastrointestinal, renal, 
hepatic, respiratory, hematological, endocrine, or cardiovascular system disease.
11. A history of malignant neoplasms (not including basal or squamous cell carcinoma of the 
skin) treated within 5 years prior to study entry, current evidence of malignant neoplasm, 
recurrent, or metastatic disease. Males with localized prostate cancer requiring no 
treatment would not be excluded.
12. A known or suspected history of drug or alcohol dependency or abuse within 
approximately the last 2 years.
13. Abnormal clinical laboratory values which are judged clinically significant by the 
investigator.
14. Hypersensitivity to donepezil or piperdine derivatives or any of the excipients.
15. Patients who cannot swallow or who have difficulty swallowing whole tablets, as tablets 
should not be broken or crushed.
16. Patients who will receive prohibited concomitant medication(s) or change dosing regimen 
of restricted concomitant medication(s) during this study.
17. Known plan for elective surgery that would require general anesthesia and administration 
of neuromuscular blocking agents, such as succinylcholine, to induce paralysis/muscle 
relaxation.
Minor surgery, such as colonoscopy or cataract surgery, will be permitted as long as it does not 
require the use of these paralytic agents.
18. Pregnant women, lactating women, or women of child-bearing potential(< 1 year post 
menopausal) who don’t agree to practice effective contraception (e.g., abstinence, an 
intrauterine device, a double-barrier method such as condom + spermicide or condom + 
diaphragm with spermicide, a contraceptive implant, an oral contraceptive, or have a 
vasectomised partner) throughout the entire study period and for 30 days after donepezil 
discontinuation, or who don’t have a negative serum â-HCG test result or a negative urine 
pregnancy test result at Screening and Baseline.
• All females will be considered to be of childbearing potential unless they are 
postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age 
group and without other known or suspected cause) or have been sterilized 
surgically (i.e. bilateral tubal ligation, hysterectomy or bilateral oophorectomy, all 
with surgery at least one month before dosing). 
• All women who are using hormonal contraceptives must have been on a stable dose 
of the same hormonal contraceptive product for at least 4 weeks prior to dosing and 
must continue to use the same contraceptive during the study and for 30 days after 
donepezil discontinuation.
19. Patients who have participated in another clinical study within 12 weeks before Screening.


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20. Any condition that would make the patient or the caregiver, in the opinion of the 
investigator, unsuitable for the study.
Study Treatment(s)
Test drug:       E2020 5 mg, 10 mg tablet
Control drug: Placebo tablet (5 mg, 10 mg)
A tablet will be taken orally once daily basically in the evening.
Placebo group:
Titration:           Placebo tablet matched to 5 mg tablet of donepezil
Maintenance:    Placebo tablet matched to 10 mg tablet or 5 mg tablet of donepezil
Donepezil group:
Titration:             5 mg tablet
Maintenance:     10 mg or 5 mg tablet
During the Maintenance period, while patients taking 10 mg/day, dose reduction to 5 mg/day 
will be permitted only when the investigator judges it difficult to continue 10 mg/day 
administration due to an occurrence of adverse event of which the causal relationship with the 
donepezil is not ruled out. The dose cannot be escalated up to 10 mg/day again.
(Open-label Extension)
Until Week 6 (Day 28- 42):       5 mg tablet of donepezil
After Week 6:    10 mg or 5 mg tablet of donepezil
After Week6, the dose can be increased to 10 mg/day. Dose reduction (from 10 mg/day to 5 
mg/day) will be also permitted when the investigator judges it difficult to continue the 10 
mg/day administration. The dose can be escalated up to 10 mg/day again.
Duration of Treatment
Screening phase:             1-4 weeks
Double-blind phase:        24 weeks (Titration: 4 weeks, Maintenance: 20 weeks)
Open-label Extension:    24 weeks (including titration of at least 4 weeks)


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Concomitant Drug/Therapy
Prohibited Concomitant Medications
12 weeks before the Screening to final day of the study
1) Anti-dementia agents (donepezil, rivastigmine, galantamine, memantine et al. except for 
the study drug)
2) Other investigational drugs
6 weeks before the Screening to final day of the study
3) Choline stimulants (cholinesterase inhibitor, choline agonists, except for topical agents)
3 weeks before the Screening to final day of the DB phase
4) Antiparkinsonian agents
5) Tricyclic antidepressants
6) Antipsychotics
7) Hypnotics (except for the short acting hypnotics defined as restricted concomitant drugs)
8) Nootropics (choline alfoscerate, acetyl-L-carnitine, oxiracetam et al.)
9) Gingko biloba
Restricted Concomitant Medications (The dose should be maintained)
3 weeks before the Screening to final day of the DB phase
1) Antidepressants (except for tricyclic antidepressants)
2) Anxiolytics
3) Hypnotics (short acting hypnotics; zolpidem, brotizolam, lormetazepam, rilmazafone, 
zopiclone, ramelteon)
Assessments
• Efficacy Assessments:
Primary efficacy variable: 
1) Cognitive function: Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(ADAS-cog)
2)   Global function: Clinicians interview-Based Impression of Change-plus (CIBIC-plus)
Secondary efficacy variables:
1) Mini-Mental Status Examination (MMSE)
2) Executive function test (Trail making test (K-TMT-e))
• Pharmacokinetics:    Not applicable
• Pharmacodynamics: Not applicable
• Pharmacokinetic-Pharmacodynamic: Not applicable
• Safety: Safety assessment will consist of determining and recording all adverse events (AEs) 
and serious adverse events (SAEs); laboratory evaluation for hematology, blood 
chemistry, and urine analysis; periodic measurement of vital signs and ECGs.
Bioanalytical Methods
Not applicable


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Statistical Methods
This section summarizes Statistical Method of Core study; DB phase.
Analysis sets
The Safety Analysis Set (SAS) is the group of subjects who received at least one dose of study 
drug and had at least one postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least one 
dose of study drug and had at least one postdose primary efficacy measurement.  
The Per Protocol Set (PPS) is the group of subjects who sufficiently complied with the 
protocol. Details of the evaluability criteria will be determined before database lock and 
treatment unblinding and will be specified in the Statistical Analysis Plan.
Efficacy analysis
The efficacy data observed from Baseline to Week 24 will be used for analysis. All statistical 
tests will be conducted at the significance level of 5.0% (two-tailed). 
The analysis will be conducted on the FAS and PPS, using the last observation carried forward 
(LOCF) method to impute missing data, and the observed cases (OC) populations at Week 24
and other time points. The analysis of FAS is primary, and that of PPS is a sensitivity analysis 
of FAS.
Primary Efficacy Analyses:
The co-primary efficacy variables are used as follows to determine whether donepezil has 
superior efficacy compared to placebo: 
・For ADAS-cog change from baseline to Week 24, an analysis of covariance (ANCOVA) 
model with baseline (covariate) and treatment (main effect) will be used for testing main 
effect. 
・For CIBIC-plus scores, least squares (LS) mean scores at Week 24 will be compared 
between groups to demonstrate numerical superiority of donepezil to placebo (the difference 
is less than 0), using ANCOVA model with CIBIS-plus (covariate) and treatment group 
(main effect).
For the measurements of each visit and the change from baseline to each visit of both 
endpoints, descriptive statistics (median, mean, standard deviation (SD), minimum, maximum, 
and number of patients with non-missing data for both variable; number and percentages of 
each score for CIBIC-plus) will be presented. Where appropriate, least square (LS) mean, 
between-treatment difference in least square (LS) means, 95% confidence intervals (CIs) for 
the difference and p value in each visit will also be presented.
Secondary Efficacy Analysis:
MMSE and executive function test score change from Baseline to Week 24 will be analyzed 
using a same ANCOVA model as is described for the ADAS-cog. Other statistical inference 
(estimating and testing) will also be analyzed in the same way with primary analysis.


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Safety analysis
The evaluation of safety parameters will be conducted on the SAS.
The incidence rates for AEs by body system, preferred term, severity, and relationship to study 
medication will be calculated. Individual vital signs will be descriptively summarized by 
treatment group and visit. Changes from Baseline to each individual post-baseline visit and to 
the final visit will be calculated. For clinical laboratory parameters, changes from Baseline to 
each visit, descriptive statistics (median, mean, standard deviation (SD), minimum, maximum,
and number of patients with non-missing data) will be presented. Shift tables depicting shifts 
in or out of the normal range, from Baseline to the final study visit, will also be provided.
ECG data will be categorized at Baseline, and results for each subject at the end of treatment 
will be compared to those at Baseline. Data on other medications used by subjects during the 
study will be collected and summarized by therapeutic class and generic components.
Interim Analyses
Not applicable
Sample Size Rationale
The primary endpoints are the change from baseline to Week 24 (LOCF) in ADAS-cog and 
the measurement at Week 24 (LOCF) of the CIBIC-plus.
The estimates of these endpoints were referred from the result of subgroup (MMSE less than 
24) in pooled data of previous double blind studies (E2020-A001-307 and E2020-A001-308).
The mean difference and standard deviation of the change from baseline to final visit in 
ADAS-cog were estimated as -2.404±5.955, using pooled data of E2020 groups (5 mg+10 
mg). When the significance level was set as 5.0% (two-tailed) and statistical power as 80.0%, 
the subject number needed to detect statistically significant difference by 2 sample t test was 
calculated to be 196 (98/arm).
On the other hand, the mean difference and the standard deviation of CIBIC-plus score at the 
final visit were estimated as -0.261±1.162, when CIBIC-plus was regarded as continuous 
measurement [scored from 1 (marked improvement) to 7 (marked worsening) point]. The 
subject number needed to reduce the probability that donepezil is inferior to placebo in point 
estimate to 2.5% or less, was calculated to be 308 (154/arm).    
Therefore, the subjects number required to achieve primary objectives simultaneously became 
308 (154/arm). In consideration of exclusion from the analysis set (approximately 5%), the 
sample size was defined as 324 (162/arm). 


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3
TABLE OF CONTENTS
1
TITLE PAGE
1
2
CLINICAL PROTOCOL SYNOPSIS
3
3
TABLE OF CONTENTS
12
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
14
5
ETHICS
16
5.1
Institutional Review Boards/Independent Ethics Committees
16
5.2
Ethical Conduct of the Study
16
5.3
Subject Information and Informed Consent
17
6
INVESTIGATORS AND STUDY PERSONNEL
17
7
INTRODUCTION
18
7.1
E2020/Donepezil hydrochloride (Aricept)
18
7.1.1
Mechanism of Action
18
7.1.2
Clinical Experience in VaD
18
7.1.3
Common Adverse Events
19
7.2
Study Rationale
20
8
STUDY OBJECTIVES
20
8.1
Co-Primary Objective
20
8.2
Secondary Objective(s)
21
9
INVESTIGATIONAL PLAN
21
9.1
Overall Study Design and Plan
21
9.1.1
Screening (SCR) Phase
22
9.1.2
Double-blind (DB) Phase
22
9.1.3
Open-label Extension (OLE) Phase
23
9.2
Discussion of Study Design, Including Choice of Control Groups
23
9.3
Selection of Study Population
23
9.3.1
Inclusion Criteria
23
9.3.2
Exclusion Criteria
25
9.3.3
Removal of Subjects from Therapy or Assessment
27
9.4
Treatments
28
9.4.1
Treatments Administered
28
9.4.2
Identity of Investigational Product(s)
30
9.4.3
Method of Assigning Subjects to Treatment Groups
31
9.4.4
Selection of Doses in the Study
31
9.4.5
Selection and Timing of Dose for Each Subject
31
9.4.6
Blinding
31
9.4.7
Prior and Concomitant Therapy
32
9.4.8
Treatment Compliance
32
9.4.9
Drug Supplies and Accountability
33
9.5
Study Assessments
34
9.5.1
Assessments
34


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9.5.2
Schedule of Procedures/Assessments
41
9.5.3
Appropriateness of Measurements
48
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest
48
9.5.5
Completion/Discontinuation of Subjects
50
9.5.6
Abuse or Diversion of Study Drug
51
9.5.7
Confirmation of Medical Care by Another Physician
51
9.6
Data Quality Assurance
51
9.6.1
Data Collection
51
9.6.2
Clinical Data Management
51
9.7
Statistical Methods
51
9.7.1
Statistical and Analytical Plans
52
9.7.2
Determination of Sample Size
56
9.7.3
Interim Analysis
57
9.7.4
Other Statistical/Analytical Issues
57
9.7.5
Procedure for Revising the Statistical Analysis Plan
57
10
REFERENCE LIST
58
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)
60
11.1
Changes to the Protocol
60
11.2
Adherence to the Protocol
60
11.3
Monitoring Procedures
60
11.4
Recording of Data
61
11.5
Identification of Source Data
61
11.6
Retention of Records
62
11.7
Auditing Procedures and Inspection
62
11.8
Handling of Study Drug
62
11.9
Publication of Results
62
11.10 Disclosure and Confidentiality
63
11.11 Discontinuation of Study
63
11.12 Subject Insurance and Indemnity
63
APPENDICES
64
APPENDIX I. NINDS-AIREN CRITERIA FOR THE DIAGNOSIS OF VASCULAR 
DEMENTIA
64
APPENDIX II. CONCOMITANT MEDICATIONS
68
APPENDIX III.  SPONSOR’S GRADING FOR LABORATORY VALUES
70
LIST OF IN-TEXT TABLES
Table 1. Clinical Laboratory Tests
39
Table 2. Schedule of Procedures/Assessments in Study E2020-K082-418:  <Core Study>
41
Table 3. Schedule of Procedures/Assessments in Study E2020-K082-418: <OLE phase>
43


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AChE
Acetylcholinesterase
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale-Cognitive subscale
AE(s)
Adverse event(s)
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
-HCG
-human chorionic gonadotropin
BP
Blood pressure
CBC
Complete blood count
CDR
Clinical Dementia Rating
CIBIC-plus
Clinician’s Interview-Based Impression of Change-plus
CIBIS
Clinician’s Interview-Based Impression of Severity
CNS
Central nervous system 
CRA
Clinical research associate
CRF(s)
Case report form(s)
CRO
Contract research organization
CT
Computerized tomography
CVD
Cerebrovascular disease
DAT
Dementia of the Alzheimer type 
DB
Double-blinded
ECG
Electrocardiogram
FAS
Full Analysis Set 
GCP
Good Clinical Practice
HbA1c
Glycosylated hemoglobin A1c
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IWRS
Interactive Web Response System
KFDA
Korea Food and Drug Administration
MedDRA
Medical Dictionary for Regulatory Activities 
MMSE
Mini-Mental Status Exam
MRI
Magnetic Resonance Imaging
NINDS-AIREN
National Institute of Neurological Disorders and Stroke-
Association Internationale pour la Recherche et l’Enseignement en 
Neurosciences (International Association for Research and 
Teaching in Neurosciences)


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OLE
Open-label extension
PET
Positron emission tomography 
PI
Principal Investigator
PPS
Per Protocol Set 
SAE(s)
Serious adverse event(s)
SAP
Statistical analysis plan 
SAS
Safety Analysis Set 
SCR
Screening
SOP
Standard operating procedure 
TIA
Transient ischemic attack
VaD
Vascular dementia
V-ADAS-cog
Vascular-Alzheimer Disease Assessment Scale-Cognitive subscale


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5
ETHICS
5.1
INSTITUTIONAL REVIEW BOARDS/INDEPENDENT ETHICS COMMITTEES
The protocol, informed consent form (ICF), and appropriate related documents must be reviewed 
and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
constituted and functioning in accordance with ICH E6 (Good Clinical Practice), Section 3, and 
any local regulations. Any protocol amendment or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval, except for changes involving only logistical or administrative 
aspects of the study (e.g., change in CRA[s], change of telephone number[s]). Documentation of 
IRB/IEC compliance with the ICH E6 and any local regulations regarding constitution and 
review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to the 
site by the sponsor or its designee (ICH E6, Section 4.4). If the IRB/IEC decides to suspend or 
terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations. If the investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report. The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide the 
IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC within the period in accordance 
with the IRB/IEC’s requirements.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC within the period in accordance with the IRB/IEC’s requirements and a detailed written 
explanation of the reasons for the termination/halt should be given.
5.2
ETHICAL CONDUCT OF THE STUDY
This study will be conducted in accordance with standard operating procedures of the sponsor (or 
designee), which are designed to ensure adherence to GCP guidelines as required by the 
following:
●
Principles of the World Medical Association Declaration of Helsinki (2008)
●
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
●
Korea Good Clinical Practice (2011)


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5.3
SUBJECT INFORMATION AND INFORMED CONSENT
The investigator is responsible for ensuring that no patient is subject to any study-related 
examination or activity before that patient has given informed consent. Written informed consent 
will be obtained from the patient (if possible) and from the patient’s legal guardian or other 
representative, prior to beginning screening activities and entering the open-label extension 
(OLE) phase. Separate written informed consent will be provided before screening and entering 
OLE phase. Even if unable to provide written informed consent, the patient must assent verbally 
to participating in the study and the record should note this assent. The caregiver must separately 
give informed consent for his or her own participation in the study. If the caregiver illiterate, 
consent will be signified by a thumbprint or another personally identifiable method acceptable in 
lieu of a signature. 
The patient, legal representative, and the caregiver will receive detailed information before the 
consent is given and the patient will receive a copy of signed document. The verbal explanation 
will cover all the elements specified in the written information provided for the patient. The 
investigator will inform the patient of the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, any potential 
discomfort, potential alternative procedure(s) or course(s) of treatment available to the subject, 
and the extent of maintaining confidentiality of the subject’s records. The patient and the 
caregiver must be given every opportunity to clarify any points he/she does not understand and if 
necessary, ask for more information. At the end of the interview, the patient and the caregiver 
may be given time to reflect if this is required, or if more time is requested. Patients and legal 
representative, and caregivers, will be required to sign and date the informed consent form. After 
completion, informed consent forms will be kept and archived by the investigator in the 
investigator’s study file.
It should be emphasized that the patient, the legal representative and/or the caregiver is at liberty 
to withdraw their consent to participate at any time, without penalty or loss of benefits to which 
the patient is otherwise entitled. Patients who refuse to give, or withdraw, written informed 
consent may not be included or continued in this study, but this will not impact on their 
subsequent care. 
The subject or the subject’s legal representative should be informed in a timely manner if new 
information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 25 investigational site(s) in Korea.
The name and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and C&R Research which is the contract research organization are listed in the
Investigator Study File provided to each site.


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7
INTRODUCTION
7.1
E2020/DONEPEZIL HYDROCHLORIDE (ARICEPT)
Donepezil (donepezil hydrochloride, E2020, Aricept) is a piperidine-based acetylcholinesterase 
(AChE) inhibitor. It has been demonstrated to be a potent and relatively specific inhibitor of 
AChE. In randomized clinical trials, donepezil has been shown to be effective and safe as a 
treatment in the management of patients with Alzheimer’s disease (AD) and Vascular dementia 
(VaD). Currently, donepezil is approved for mild to moderate AD in more than 90 countries, for 
severe AD in about 30 countries, and for VaD in 12 countries. In Korea, the indication of Aricept 
is as follows:
[Indication] For the symptomatic treatment of Alzheimer’s disease and symptomatic 
improvement of vascular dementia (with cerebrovascular disease).
7.1.1
Mechanism of Action
Donepezil is a selective and reversible inhibitor of AChE both in the periphery as well as in the 
central nervous system (CNS). It acts to increase the central cholinergic activity in the brain. 
Inhibitor of AChE activity prevents the breakdown of acetylcholine and results in increased 
acetylcholine concentration at the synaptic site. Biochemical studies have demonstrated that 
donepezil binds selectively to AChE, rather than butyrylcholinesterase, and reversibly inhibits 
AChE activity in the periphery as well as in the rat cerebral cortex, hippocampus, striatum, and 
hypothalamus. Donepezil binding to AChE has also been shown in human brain by positron 
emission tomography (PET) imaging.
7.1.2
Clinical Experience in VaD
Three large-scale clinical studies of VaD have been conducted to assess the efficacy and safety 
of donepezil in VaD by Eisai. These studies, E2020-A001-307, E2020-A001-308 and E2020-
A001-319, were randomized, double-blind, placebo-controlled trials. A diagnosis of probable or 
possible VaD according to NINDS-AIREN criteria was required for enrollment (i.e., evidence of 
dementia and a probable or possible relationship between dementia and CVD). Patients with a
prior diagnosis of AD and subsequent cognitive impairment due to stroke or CVD were 
excluded. In the first 2 studies, E2020-A001-307 and E2020-A001-308, patients were 
randomized to receive placebo, donepezil 5 mg/day or donepezil 10 mg/day (5 mg/day for first 
28 days). Efficacy assessments included the Alzheimer's Disease Assessment Scale-cognitive 
subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Clinician’s 
Interview-Based Impression of Change-plus version (CIBIC-plus).  
In Study 307, a total of 603 patients were enrolled (199 placebo, 198 donepezil 5 mg/day, 206 
donepezil 10 mg/day); 425 (70%) had probable VaD and 30% had possible VaD. Both 
donepezil-treated groups showed significant improvements in cognitive function compared with 
placebo for the ADAS-cog. The donepezil 5 mg/day group showed significant improvements in 


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global function compared with placebo on the CIBIC-plus. The patient population had a high 
incidence of CVD and cardiovascular disease. Donepezil was well tolerated in this population, 
with low withdrawal rates due to adverse events and a similar incidence of cardiovascular AEs 
across all treatments. 
In Study 308, a total of 616 patients were enrolled (193 placebo, 208 donepezil 5 mg/day, 215 
donepezil 10 mg/day); 468 (76%) had probable VaD and 24% had possible VaD. Both 
donepezil-treated groups showed significant improvements in cognitive function compared with 
placebo on the ADAS-cog and MMSE. Greater improvements on the CIBIC-plus were observed 
with both donepezil groups than with the placebo group. Donepezil was well tolerated in this 
population (of whom 90% had co-morbid cardiovascular disease), with low withdrawal rates due 
to adverse events (placebo, 8.8%; donepezil 5 mg, 10.1%; donepezil 10 mg, 16.3%).
In Study 319, patients were randomized to receive placebo or donepezil 5 mg/day. Efficacy 
assessments included the Vascular-Alzheimer’s Disease Assessment Scale-Cognitive Subscale
(V-ADAS-cog), the ADAS-cog, the MMSE, and the CIBIC-plus. A total of 974 patients were 
enrolled (326 placebo, 648 donepezil 5 mg/day). Donepezil group showed significant 
improvements in cognitive function compared with placebo on the V-ADAS-cog and ADAS-cog, 
however, donepezil group did not show significant improvements in global function compared 
with placebo on the CIBIC-plus. Donepezil was well tolerated in this population with low 
withdrawal rates due to adverse events (placebo, 5.5%; donepezil 5 mg, 11%)
7.1.3
Common Adverse Events 
In Study 307, the most common adverse events were diarrhea (14.1%), infection (13.8%),
accidental injury (12.9%), nausea (10.6%), and urinary tract infection (10.0%). Accidental
injury, infection, and urinary tract infection occurred with similar frequency across the 3 
treatment groups. Diarrhea and nausea occurred more frequently in the donepezil treatment 
groups than in the placebo group. Of these, a dose-related effect was observed only for nausea.
In Study 308, the four most commonly observed adverse events consisted of the following: 
infection (17.3% of patients in the 5 mg donepezil group, 14.0% of patients in the 10 mg 
donepezil group and 13.5% of those in the placebo group), diarrhea (11.5% of patients in the 5 
mg donepezil group, 18.6% of patients in the 10 mg donepezil group and 10.4% of those in the 
placebo group), accidental injury (16.8% of patients in the 5 mg donepezil group, 12.6% of 
patients in the 10 mg donepezil group and 9.8% of those in the placebo group), and nausea 
(11.1% of patients in the 5 mg donepezil group, 16.7% of patients in the 10 mg donepezil group 
and 7.8% of those in the placebo group). Other adverse events that occurred significantly more 
frequently in the donepezil groups included abnormal dreams, insomnia and rhinitis.
In Study 319, the most common events in the donepezil group were diarrhea (11.7% versus 7.4% 
for placebo), infection (11.6% versus 11.0% for placebo), nausea (9.9% versus 4.3% for 
placebo), accidental injury (9.0% versus 10.1% for placebo), urinary tract infection (8.8% versus 
10.1% for placebo), asthenia (8.2% versus 7.1% for placebo), headache (7.9% versus 6.4% for 


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placebo), and pain (7.6% versus 8.0% for placebo). The occurrence rates were statistically 
significantly higher in the donepezil group than the placebo group for the following events: 
diarrhea (11.7% versus 7.4%), nausea (9.9% versus 4.3%), abnormal dreams (3.4% versus 
0.6%), hypertonia (3.2% versus 0.3%), and leg cramps (2.6% versus 0.6%). Most adverse events 
were mild to moderate. 
In Study 307, the mortality rates were 2/198 (1.0%) on donepezil hydrochloride 5 mg, 5/206 
(2.4%) on donepezil hydrochloride 10 mg and 7/199 (3.5%) on placebo. In Study 308, the 
mortality rates were 4/208 (1.9%) on donepezil hydrochloride 5 mg, 3/215 (1.4%) on donepezil 
hydrochloride 10 mg and 1/193 (0.5%) on placebo. In Study 319, the mortality rates were 11/648 
(1.7%) on donepezil hydrochloride 5 mg and 0/326 (0%) on placebo. The total mortality rate for 
the three VaD studies in the donepezil hydrochloride group (1.7%) was numerically higher than 
in the placebo group (1.1%), however, this difference was not statistically significant. The 
majority of deaths in patients taking either donepezil hydrochloride or placebo appear to result 
from various vascular related causes, which could be expected in this elderly population with 
underlying vascular disease. An analysis of all serious non-fatal and fatal vascular events showed 
no difference in the rate of occurrence in the donepezil hydrochloride group relative to placebo. 
7.2
STUDY RATIONALE
Three large-scale clinical studies of VaD have been conducted to assess the efficacy and safety 
of donepezil in VaD. In Study 307, both donepezil-treated groups showed significant 
improvements in cognitive function compared with placebo for the ADAS-cog. The donepezil 5 
mg/day group showed significant improvements in global function compared with placebo on the 
CIBIC-plus. In study 308, both donepezil-treated groups showed significant improvements in 
cognitive function compared with placebo on the ADAS-cog. Greater improvements on the 
CIBIC-plus were observed with both donepezil groups than with the placebo group. In Study 
319, the donepezil 5 mg/day group showed significant improvement in the cognitive function for 
the V-ADAS-cog and ADAS-cog. However, the donepezil 5 mg/day group did not show the 
significant result of the CIBIC-plus.  
Donepezil has been used for vascular dementia (with cerebrovascular disease) in Korea since 
2005. However, three pivotal studies lacked consistency in efficacy on global function measured 
by CIBIC-plus.
The objectives of this multi-center clinical trial in Korea are to confirm the efficacy of donepezil 
on cognitive and global function in patients with VaD.
8
STUDY OBJECTIVES
8.1
CO-PRIMARY OBJECTIVE
1) To confirm that donepezil hydrochloride (E2020) has superior efficacy compared with 
placebo in improving cognitive function, as measured by ADAS-cog, in patients with 
dementia associated with cerebrovascular disease (VaD).


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2) To demonstrate that donepezil hydrochloride (E2020) has superior efficacy compared with 
placebo in improving global function, as measured by CIBIC-plus, in patients with VaD.
8.2
SECONDARY OBJECTIVE(S)
To evaluate the efficacy (as measured by MMSE and executive function test) and safety of 
E2020 compared with placebo, in patients with VaD.
9
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study with 
an open-label extension. The main part of the study consists of 2 phase; screening phase (SCR;1 
to 4 weeks), and double-blind phase (DB;24 weeks, placebo-controlled). DB phase includes 2 
periods; titration and maintenance. The duration of titration period is 4 weeks.
Prior to performing any procedures or evaluation, written informed consent will be obtained. Up 
to 4 weeks prior to randomization, prospective patients will be screened to confirm their 
diagnosis and suitability for study entry. Subjects who continue to meet all of the inclusion and 
none of the exclusion criteria will be randomly assigned to receive either donepezil or placebo.      
Donepezil and placebo will be taken once daily in the evening for the duration of their 
participation in the study. 5 mg of donepezil will be administrated in the titration period and then 
the dose will be increased to 10 mg at Week 4 (Day 28-35) according to investigator's clinical 
judgment. During the maintenance period, dose reduction to 5 mg/day will be permitted only 
when 10 mg/day is intolerable due to adverse events. In this case, the dose cannot be escalated 
up to 10 mg/day again.


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(Open-label Extension)
Subjects, who have completed the double-blind (DB) phase and want to continue the study 
participation, can be enrolled in the 24-week open-label extension phase. In this phase, treatment 
is initiated at 5 mg/day, and the dose is maintained until Week 6 (Day 28-42). After assessing 
clinical response during the period by examination, the dose can be increased to 10 mg/day. 
Dose reduction (from 10 mg/day to 5 mg/day) is permitted when the investigator judges it 
difficult to continue the 10 mg/day administration. It is possible to increase the dose to 10
mg/day again. Subjects will visit the study institution at Week 6, 12, and 24.
9.1.1
Screening (SCR) Phase
The SCR Phase will last for 1-4 weeks and will include a SCR period and a Baseline visit.
9.1.1.1
Screening Period
Screening will occur between 1 week and 4 week before the patients will be enrolled. The 
purpose of the SCR period is to obtain informed consent and to establish protocol eligibility. 
Informed consent will be obtained after the study has been fully explained to each patient, 
caregiver, and patient’s legal guardian before the conduct of any screening procedures or 
assessments. Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3. Results of the screening activities must be recorded on the appropriate case report 
form (CRF) to indicate whether the subject is eligible to participate in the study and to provide 
reasons for screen failure, if applicable.
Investigators should ensure that the patient and caregiver will be instructed that the patient is to 
discontinue use of all donepezil medication from previous prescriptions, so as to ensure that the 
patient does not consume any doses of donepezil other than or in addition to study.
9.1.1.2
Baseline visit
Investigators will reconfirm the inclusion/exclusion criteria and perform the assessments and 
evaluations to the subjects. Subjects whose screening assessments and evaluations are completed 
and reviewed by the principal investigator and who continue to meet all of the 
inclusion/exclusion criteria (Sections 9.3.1 and 9.3.2) will enter the DB phase. They will be 
randomly assigned in 1:1 ratio to receive either donepezil or placebo by Interactive Web 
Response System (IWRS).
9.1.2
Double-blind (DB) Phase
The duration of the DB phase will be 24 weeks and will include 2 periods: Titration and 
Maintenance. The duration of titration period is 4 weeks.
9.1.2.1
Titration Period
During the Titration period, subjects assigned to donepezil group will be started E2020 on 5 
mg/day. On the other hand, subjects assigned to placebo group will be started placebo tablet 


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matched to 5 mg tablet. The duration of titration period is 4 weeks. The dose will be increased to 
10 mg according to investigator's clinical judgment at Week 4 (Day 28-35).
9.1.2.2
Maintenance Period
During the Maintenance period, subjects will continue treatment with 10 mg of donepezil or 
placebo. Dose reduction to 5 mg/day will be permitted only when 10 mg/day is intolerable due to 
an occurrence of adverse events of which the causal relationship with the study drug is not ruled 
out. In this case, the dose cannot be escalated up to 10 mg/day again. The duration of 
maintenance period is 20 weeks. Subjects will visit the study institution at Week 6, 12, 18, and 
24.
9.1.3
Open-label Extension (OLE) Phase
Before starting the OLE phase, subjects have to provide written informed consent to participate 
in OLE phase. Subjects, who have completed the DB phase, can be enrolled in the 24-week OLE
phase. In this phase, treatment is initiated at 5 mg/day, and the dose is maintained until Week 6 
(Day 28-42; for at least 4 weeks). After assessing clinical response at Week 6 visit, the dose can 
be increased to 10 mg/day. Dose reduction (from 10 mg/day to 5 mg/day) is permitted when the 
investigator judged it difficult to continue the 10 mg/day administration. It is possible to increase 
the dose to 10 mg/day again. Subjects will visit the study institution at Week 6, 12, and 24.
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS
Randomization will be used in this study to avoid bias in the assignment of subjects to treatment, 
to increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are balanced across treatment groups, and to ensure the validity of 
statistical comparisons across treatment groups. Blinding to treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints.
The double-blind, parallel-group design is considered to be appropriate for the comparison of 
efficacy and safety in patients receiving donepezil with that in patients receiving placebo. The 
intended sample size has been selected to achieve sufficient power for comparisons of efficacy. 
9.3
SELECTION OF STUDY POPULATION
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion criteria 
will not be eligible to receive donepezil.
9.3.1
Inclusion Criteria
Patients who meet all of the following criteria will be eligible for inclusion in the study:
1.  Male or female, age ≥ 40 years at the time of informed consent.


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2. Possible or probable dementia associated with cerebrovascular disease as defined by 
NINDS-AIREN Criteria with dementia of greater than 3 months duration.
3.  Radiological evidence of cerebrovascular disease.
4. Mini-Mental State Examination (MMSE) score is ≥ 10 and ≤ 24 at both Screening and 
Baseline.
5.  Clinical Dementia Rating (CDR) ≥ 1.
6.  Outpatients who are physically healthy, and ambulatory or ambulatory-aided (i.e., walker, 
cane or wheelchair). 
7. Written informed consent (IC) is obtained from the patient (if possible) and from the 
patient’s legal guardian prior to being exposed to any study-related procedures. Even if 
unable to provide written IC, the patient must assent verbally to participating in the study 
and the record should note this assent. The caregiver must separately provide IC for 
his/her own participation in the study.
8.  Patients having caregivers who submit written consent to cooperate with this study, have 
regular contact with the patient (i.e., an average of ≥4 hours/day and ≥3 days/week), 
provide patients’ information necessary for this study, ensure the regular administration of 
assigned donepezil, as well as all concomitant therapies, at the correct dose, and escort the 
patients on required visits to study institution.  
If, during the study, the designated caregiver relinquishes his/her responsibilities to 
another caregiver, the new caregiver must provide IC, and otherwise similarly qualify for 
inclusion in the study. If no replacement caregiver is available who meets the caregiver 
criteria, the subject must be discontinued from this study. 
9. Patients who can visit study institution as required following with investigator’s 
instruction.
10.  Patients who have vision, hearing, speech, motor function and comprehension sufficient to 
be able to comply with testing procedures (glasses, contact lens, and hearing aid 
permissible).
11. Patients who meet prohibition/restriction of using concomitant medications before 
Screening.
12. Comorbid medical conditions are clinically stable prior to Baseline, unless otherwise 
specified. The following situations should be given particular attention;
               a. Patients with risk factors of hypertension and cardiac disease may be enrolled, 
provided that hypertension is well controlled by medication (supine diastolic blood 
pressure < 95 mmHg) and cardiac disease (e.g. angina pectoris, congestive heart 
failure, or right bundle branch block) is stable on appropriate medication for at least 
12 weeks prior to Screening. Peripheral vascular disease must have been stable for 
12 weeks prior to Screening. No elective surgical procedures should be planned 
during the course of the study (e.g., vascular bypass procedures or coronary artery 
bypass surgery).


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b. Patients with diabetes mellitus or risk factors for diabetes mellitus may be enrolled, 
provided that the patient’s disease is stable and that there have been no recent 
(within 12 weeks of Screening) hospitalizations for diabetic ketoacidosis, 
hyperosmolar coma, or hyperglycemia. Patients with non-insulin-dependent diabetes 
may b enrolled if controlled on diet or oral medications. All diabetic patients must 
have an HbA1c concentration of ≤ 10% and a random serum glucose concentration 
of ≤ 250 mg/dL at Screening.
             c.  Patients with risk factors of stroke may be enrolled, provided that the disease process 
has been stable or controlled on medication for greater than 12 weeks prior to 
Screening.  Patients receiving anticoagulation with warfarin are eligible for 
inclusion in the study if the International Normalized Ratio (INR) for prothrombin 
time is within the therapeutic range for prophylaxis (1.4-3.0) and the dose of 
warfarin is stable. Patients with prosthetic heart valves, who require full 
anticoagulation, should have a stable (≥ 3 months) INR in the range of 2.5-3.5.
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded:
1. Anti-dementia drug therapy (cholinesterase inhibitors or memantine) within 12 weeks 
prior to Screening.
2. Clinical and/or radiological evidence for other serious degenerative neurological disorders 
or neuropsychiatric disorders.
e.g., Alzheimr’s disease, Parkinson’s disease, Huntinton’s disease, Pick’s disease, 
Creutzfeld-Jacob disease, dementia with Lewy Bodies, normal pressure 
hydrocephalus, olivopontocerebellar atrophy, multiple system atrophy, brain 
tumor, progressive supranuclear palsy, idiopathic seizure disorder, subdural 
hematoma, multiple sclerosis, active cerebral vasculitis, schizophrenia, and 
bipolar or unipolar depression
3. Known human immunodeficiency virus disease, neurosyphilis, or a history of significant 
head trauma followed by persistent neurological deficits or known structural brain 
abnormalities.
4. Hypothyroidism at Screening
Patients may be enrolled, provided that they are on a stable dose of medication for at last 12 
weeks prior to Screening, have normal thyroid stimulating hormone and free thyroxine at 
Screening, and are considered euthyroid. 
5. Vitamin B12 or folate deficiency at Screening. 
Patients who are currently receiving B12 supplementation by oral or parenteral injection may be 
included, provided that dosing regimen has not changed for 12 weeks, plasma B12 levels 
are normal or above normal and there is documented evidence of continued cognitive 
deterioration after initiation of B12 treatment.


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6. Evidence of a new TIA or stroke that occurs within 12 weeks prior to Screening, even if 
the symptoms are minor and do not require hospitalization, are excluded.
These patients may subsequently become eligible for inclusion, if no new stroke or TIA is noted 
for 12 weeks (3 months) and all other criteria are net.  
7. Supine diastolic blood pressure ≥ 95 mmHg at Screening or Baseline.  
8. Complication of sick sinus syndrome, abnormal auricular and atrioventricular junction 
conductions (AV block, ≥ II ventricular block, etc.), or with a prolonged QT/QTc interval 
(> 450 ms) as demonstrated by a repeated ECG
9. A history of life-threatening arrhythmias (e.g., unstable atrial flutter, unstable atrial 
fibrillation, ventricular tachycardia, ventricular fibrillation, or torsade de pointes).
10.
Evidence of clinically significant, severe, active, or unstable gastrointestinal, renal, 
hepatic, respiratory, hematological, endocrine, or cardiovascular system disease.
11. A history of malignant neoplasms (not including basal or squamous cell carcinoma of the 
skin) treated within 5 years prior to study entry, current evidence of malignant neoplasm, 
recurrent, or metastatic disease. Males with localized prostate cancer requiring no 
treatment would not be excluded.
12. A known or suspected history of drug or alcohol dependency or abuse within 
approximately the last 2 years.
13. Abnormal clinical laboratory values which are judged clinically significant by the 
investigator.
14. Hypersensitivity to donepezil or piperdine derivatives or any of the excipients.
15. Patients who cannot swallow or who have difficulty swallowing whole tablets, as tablets 
should not be broken or crushed.
16. Patients who will receive prohibited concomitant medication(s) or change dosing regimen 
of restricted concomitant medication(s) during this study.
17. Known plan for elective surgery that would require general anesthesia and administration 
of neuromuscular blocking agents, such as succinylcholine, to induce paralysis/muscle 
relaxation.
Minor surgery, such as colonoscopy or cataract surgery, will be permitted as long as it does not 
require the use of these paralytic agents.
18. Pregnant women, lactating women, or women of child-bearing potential (< 1 year post 
menopausal) who don’t agree to practice effective contraception (e.g., abstinence, an 
intrauterine device, a double-barrier method such as condom + spermicide or condom + 
diaphragm with spermicide, a contraceptive implant, an oral contraceptive, or have a 
vasectomised partner) throughout the entire study period and for 30 days after donepezil
discontinuation, or who don’t have a negative serum β-HCG test result or a negative urine 
pregnancy test result at Screening and Baseline.
• All females will be considered to be of childbearing potential unless they are 
postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age 
group and without other known or suspected cause) or have been sterilized 


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surgically (i.e. bilateral tubal ligation, hysterectomy or bilateral oophorectomy, all 
with surgery at least one month before dosing). 
• All women who are using hormonal contraceptives must have been on a stable dose 
of the same hormonal contraceptive product for at least 4 weeks prior to dosing and 
must continue to use the same contraceptive during the study and for 30 days after 
donepezil discontinuation.
19.
Patients who have participated in another clinical study within 12 weeks before 
Screening.
20. Any condition that would make the patient or the caregiver, in the opinion of the 
investigator, unsuitable for the study. 
9.3.3
Removal of Subjects from Therapy or Assessment
  1) Scheduled Termination
The patient will be considered to have completed the DB phase after 24 weeks of double-
blind treatment and completion of the Week 24 visit procedures. Patients who have 
completed the DB phase can be enrolled in the OLE phase. The patient will be considered 
to have completed the OLE phase after 24 weeks of open-label treatment and completion 
of the Week 24 visit procedures. Upon completion of DB phase or OLE phase, and after 
resolution of any AEs or laboratory abnormalities that may be present on the last study 
day, the patient will be considered to have completed the study.
  2) Unscheduled Termination or Removal of Patients from the Study
In accordance with the Declaration of Helsinki, patients have the right to withdraw from 
the study at any time and for any reason. The principal investigator (PI) and/or the 
sponsor have the right to withdraw a patient from the study for any of the following 
reasons:
                1. Adverse event (AE)
                2. At the request of the patient, PI, or Sponsor, whether for administrative or 
other reasons
                3. Protocol violation or unreliable, disruptive behavior
                4. Patients could be considered for withdrawal at any time from the study for 
lack of efficacy or evidence of no therapeutic benefit.    
                5. Patients could be considered for withdrawal when the patients receive 
prohibited/restricted concomitant medication. 
If a patient decides to discontinue participation, or is removed from the study prior to 
completion, the final discharge procedures should be conducted. Specific events leading 
to discontinuation and any related test results will be recorded and explained in the CRF.


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If a patient decides to discontinue study medication for any reason, he/she will be
instructed to immediately notify the PI. In such cases, an early termination visit must be 
scheduled as soon as possible, preferably within 1 to 3 days following discontinuation of 
study medication. 
The date and time of the last drug dose and all observations collected up to the time of 
termination will be recorded in the source document and the corresponding CRF along 
with the reason for termination. Procedures at discharge will be conducted, if possible, as 
described under Scheduled Termination.  
9.4
TREATMENTS
9.4.1
Treatments Administered
The following treatments will be administered to subjects in each study period. A tablet will be 
taken orally once daily basically in the evening.
(DB Phase)
Placebo group:
Titration:           Placebo tablet matched to 5 mg tablet of donepezil
Maintenance:    Placebo tablet matched to 10 mg tablet or 5 mg tablet of donepezil
Donepezil group:
Titration:             5 mg tablet
Maintenance:     10 mg or 5 mg tablet
During the Maintenance period, while patients taking 10 mg/day, dose reduction to 5 mg/day 
will be permitted only when the investigator judges it difficult to continue 10 mg/day 
administration due to an occurrence of adverse event of which the causal relationship with the 
donepezil is not ruled out. The dose cannot be escalated up to 10 mg/day again.
(Open-label Extension)
Until Week 6 (Day 28- 42):     5 mg tablet of donepezil
After Week 6:    10 mg or 5 mg tablet of donepezil
After Week 6, the dose can be increased to 10 mg/day. Dose reduction (from 10 mg/day to 5 
mg/day) will be also permitted when the investigator judges it difficult to continue the 10 
mg/day administration. It is possible to increase the dose to 10 mg/day again.
The study medication will be dispensed to patient at the Baseline, at Week 4, 6, 12 and 18 in DB 
phase. In OLE phase, the study medication will be dispensed to patient at OLE Week 0, 6, and 
12. Patients should be instructed to take their study medication with approximately eight (8) 


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ounces or 225 ml of a non-alcoholic beverage (preferably water). Study medication must be 
administered whole. Tablets cannot be split, broken or crushed prior to administration.


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9.4.2
Identity of Investigational Product(s)
The donepezil 5 mg and 10 mg formulations and the corresponding matching placebo for each 
formulation will be supplied as tablets. They will be manufactured by Daewoong Co. LTD.
Description: 5 mg - white, round, film-coated tablet, 10 mg - yellow, round, film-coated tablet
The sponsor will provide the study drugs packaged in a double-blind configuration in labeled 
containers (bottles). Each subject’s study drug will consist of either donepezil or the matching 
placebos. In OLE phase, the study drugs will be packed in open-labeled containers (bottles). The 
study drug will consist of donepezil only.  
Packaging container: bottle packaging
materials for bottle: high-density polyethylene (HDPE), polypropylene (PP), polystyrene (PS)
materials for cap: PP, LDPE (low-density polyethylene), acrylonitrile butadiene styrene (ABS)
9.4.2.1
Chemical Name, Structural Formula of E2020
●
Test drug code: E2020
●
Generic name: Donepezil Hydrochloride 
●
Chemical 
name: 
(±)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxyindan-1-one 
monohydrochloride
●
Molecular formula: C24H29NO3.HCl
●
Molecular weight: 415.96
●
Structural formula: 
N
H3CO
H3CO
O
·HCl
9.4.2.2
Comparator Drug
Placebo tablet matched to 5 mg or 10 mg tablet
9.4.2.3
Labeling for Study Drug
The sponsor will provide study drug packed in labeled sheets to the pharmacist in investigational
site. Labeling of study drug is in accordance with article 75 clause 6 of Enforcement Regulations 
of the Pharmaceutical Affairs Act in Korea and will include the following information. 
1) Cautionary statement for ‘Investigational drug’  
2) Product code or generic name of active ingredient
3) Lot number and expiration date or retest date
      4) Storage method  
      5) The name and address of the approved party for the clinical trial
      6) Cautionary statement for ‘It is not allowed to use for other purpose except clinical trial’


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9.4.2.4
Storage Conditions
Donepezil will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the donepezil is maintained within an 
established room temperature range, 1°C to 30°C.
9.4.3
Method of Assigning Subjects to Treatment Groups
At the time of the Baseline visit, patients meeting the eligibility criteria will be randomly 
assigned (1:1) to either donepezil group or placebo group by IWRS system according to a 
computer-generated randomization code generated by an independent statistician.  
The list of patient randomization codes will be generated using PROC PLAN in the SAS®
procedures. A stratified block randomization approach will be used for the randomization with 
MMSE (≤ 19, 20 ≤) as stratum in each study site.
(Open-label extension)
This is an open-label extension phase. Subjects, who have completed the DB phase and have 
consented to continue participation of the study, can be enrolled in the 24-week open-label 
extension phase. All subjects who provide signed informed consent to participate in this phase
will be assigned to receive active drug. There is no randomization in this phase.
9.4.4
Selection of Doses in the Study
Donepezil is currently approved for the treatment of dementia associated with Alzheimer’s 
disease and for symptom improvement in vascular dementia at 5 mg/day and 10 mg/day in 
Korea. The dose can be escalated to 10 mg after assessing the clinical response of donepezil. 
Also, the maximum tolerance dose is 10 mg/day. Thus, for this study, placebo, 5 mg and 10 mg 
will be the doses studied.  
9.4.5
Selection and Timing of Dose for Each Subject
After the baseline evaluations have been completed, subjects start taking study medication in the 
evening of the baseline. Study drugs will be taken orally once daily basically in the evening 
throughout the study.
9.4.6
Blinding
During the DB Phase, subjects and all personnel involved with the conduct and interpretation of 
the study, including investigators, site personnel, and sponsor staff will be blinded to the 
treatment codes. Randomization data will be kept strictly confidential, filed securely by an 
appropriate group with the sponsor or CRO and accessible only to authorized persons (e.g., Eisai 
Global Safety) until the time of unblinding, per standard operating procedure (SOP).


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9.4.7
Prior and Concomitant Therapy
9.4.7.1
Prohibited and Restricted Concomitant Therapies and Drugs
1) Prohibited concomitant medication
12 weeks before the Screening to final day of the study
①Anti-dementia agents: Donepezil, rivastigmine, galantamine, memantine, except for the 
study drug
②Other investigational drugs
6 weeks before the Screening to final day of the study
③Choline stimulants (cholinesterase inhibitor, choline agonists, except for topical agents)
3 weeks before the Screening to final day of the DB phase
④Antiparkinsonian agents
⑤Tricyclic antidepressants
⑥Antipsychotics
⑦Hypnotics (except for the short actin hypnotics defined as restricted concomitant drugs)
⑧Nootropics (choline alfoscerate, acetyl-L-carnitine, oxiracetam et al.)
⑨Gingko biloba
2) Restricted concomitant medications (The dose should be maintained)
3 weeks before the Screening to final day of DB phase
①Antidepressant (except for tricyclic antidepressants)
②Anxiolytics
③Hypnotics (short acting hypnotics; zolpidem, brotizolam, lormetazepam, rilmazafone, 
zopiclone, ramelteon )
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study. Clinical research 
associates (CRAs) will review treatment compliance during site visits and at the completion of 
the study.
At Week 4, 6, 12, 18 and 24 in DB phase and Week 6, 12, and 24 in OLE phase, the study 
medication from the previous treatment period will be returned to the investigator. The 
medication will be inventoried and the percent compliance calculated by dividing the number of 
doses removed from the sheets by the number of days of the treatment period. For example, if 
between weeks 6 and 12, the patient had a 42-day interval between clinic visit and 40 doses of 
medication have been removed and administered, the patient is 95% compliant (40/42 x 100= 
95%). If compliance is less than 80% or greater than 120% at any visit, the reason(s) must be 
noted on the appropriate page of the CRF and in the source documents. If there are two 
consecutive visits where compliance is < 80% or > 120%, the patient will be discontinued from 
the study for non-compliance. 


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9.4.9
Drug Supplies and Accountability
The investigator and the study staff will be responsible for the accountability of study drugs
(dispensing, inventory, and record keeping) following the sponsor’s instructions and adherence 
to Good Clinical Practice (GCP) guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow study drugs to be used other than as directed 
by this protocol. Study drugs supplies will not be dispensed to any individual who is not enrolled 
in the study.  
The site must maintain an accurate and timely record of the following: receipt of study drugs, 
dispensing of study drugs supplies to the subject, collection and reconciliation of unused study 
drugs supplies that are either returned by the subjects or shipped to site but not dispensed to 
subjects, and return of reconciled study drugs supplies to the sponsor or (where applicable) 
destruction of reconciled study drugs supplies at the site.  This includes, but may not be limited 
to: (a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study drugs that 
occurs at the site.  All forms will be provided by the sponsor. Any comparable forms that the site 
wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection by a 
designated representative of the sponsor or a representative of a health authority (e.g., KFDA).  
As applicable, all unused study drugs supplies and empty and partially empty containers from 
used study drugs are to be returned to the investigator by the subject and together with unused 
study drugs that were shipped to the site but not dispensed to subjects are to be returned to the 
sponsor’s designated central or local depot(s) during the study or at the conclusion of the study, 
unless provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s). Approval for destruction to 
occur at the site must be provided by the sponsor in advance. Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed and sealed and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may be 
removed from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following the 
site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.


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9.5
STUDY ASSESSMENTS
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit. Demography 
information includes date of birth (or age), sex, race/ethnicity.
9.5.1.2
Baseline Assessments
MEDICAL HISTORY 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit. All pertinent medical and surgical history within 1 year must be noted on the appropriate 
CRF.
DIAGNOSIS
Patient will be diagnosed as possible or probable dementia associated with cerebrovascular 
disease according to NINDS-AIREN Criteria.
HACHINSKI ISCHEMIA SCALE
The Hachinski Ischemia Scale is a simple clinical tool widely used in the differentiation of 
Alzheimer’s disease and ischemic vascular dementia (Swanwick et al., 1996). The scale consists 
of 13 criteria: abrupt onset, stepwise deterioration, fluctuating course, nocturnal confusion, 
preservation of personality, depression, somatic complaints, emotional incontinence, history of 
hypertension, history of strokes, associated arteriosclerosis, focal neurological symptoms, and 
focal neurological signs. The clinician marks all items that are present in the patient. Criteria are 
weighted individually and scored as either 1 (no) or 2 (yes)
NEUROLOGICAL EXAMINATION
A comprehensive neurological examination will be performed at the Screening Visit. The 
examination will include the evaluation of the cranial nerves (including visual fields), motor, 
sensory, brainstem, cerebellar and autonomic functions. 
CRANIAL MRI OR CT
Cranial MRI or CT should be obtained as part of the Screening activities, if an MRI or CT was 
not obtained within the past 6 months. If obtained as part of Screening, a scan must be obtained 
at least 7 days prior to the Baseline visit. 
CDR (CLINICAL DEMENTIA RATING)
The Clinical Dementia Rating (CDR) will be performed at the Screening Visit. The clinical 
Dementia Rating (CDR) is a global scale developed to clinically denote the presence of 
Dementia of the Alzheimer type (DAT) and stage its severity. The clinical protocol incorporates 
semi-structured interviews with the patient and informant to obtain information necessary to rate 


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the subject’s cognitive performance in six domains: memory, orientation, judgment and problem 
solving, community affairs, home and hobbies and personal care. Criterion validity for both the 
global CDR and scores on individual domains has been demonstrated, and the CDR also has 
been validated neuropathologically, particularly for the presence or absence of dementia. 
9.5.1.3
Efficacy Assessments
Primary efficacy variable:
1) Cognitive function: Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-
cog)
ADAS-cog will be assessed at Visit 2, 3, 5, 6, and 7 (Week 0, 4, 12, 18, and 24). 
Every ADAS-cog test for one subject should be administered by one rater throughout 
the study. 
2) Global function: Clinicians Interview-Based Impression of Change-plus (CIBIC-plus)
CIBIC-plus will be assessed at Visit 2, 3, 5, and 7 (Week 0, 4, 12 and 24). CIBIS will 
be assessed at Visit 2 (Week 0). CIBIS and every CIBIC for one subject should be 
evaluated by one independent rater throughout the study. Clinical information about 
the subject from any source can be used for the CIBIS, but not at any other time for 
the CIBIC during the study. The rater will refer to the CIBIS to complete the CIBIC. 
Secondary efficacy variables:
1) Mini-Mental Status Examination (MMSE) (Folstein et al., 1975)
The MMSE is a brief test for measuring the cognitive state of the patient. This 30-
point test includes items evaluating orientation to time and place, recall of objects, 
attention, language, and conversational abilities. This test is conducted with the 
patient by a trained clinician. The MMSE will be assessed every clinic visits. Every 
test for one subject should be administered by one rater throughout the core study
(Baseline and DB phase).
2) Executive function test (Trail making test)
Executive function test (Trail making test (K-TMT-e)) will be assessed at Visit 2, 5,
and 7 (Week 0, 12, and 24). Every test for one subject should be administered by one 
rater throughout the study.
These will be assessed by trained investigators or psychometrists.
9.5.1.4
Pharmacokinetic, 
Pharmacodynamic, 
and 
Pharmacogenomic/Pharmacogenetic 
Assessments
Not applicable


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9.5.1.5
Safety Assessments
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered an investigational product. During clinical studies, adverse event 
information will be collected after signing of informed consent in order to collect study-
associated events. An AE does not necessarily have a causal relationship with the medicinal 
product. For this study, the study drug(s) is 5 mg donepezil and corresponding matching placebo, 
as well as donepezil 10 mg and corresponding matching placebo.
The criteria for identifying AEs are:
●
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product
●
Any new disease or exacerbation of an existing disease
●
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
●
Recurrence of an intermittent medical condition (e.g., headache) not present pretreatment 
(Baseline)
●
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not.
A laboratory result should be considered by the investigator to be an AE if it:
●
Results in the withdrawal of study drug
●
Results in withholding of study drug pending some investigational outcome
●
Results in an intervention, based on medical evaluation (e.g., potassium supplement for 
hypokalemia)
●
Results in any out of range laboratory value that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile
All AEs observed during the study will be reported on the CRF. All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit. Serious AEs will be collected for 30 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE. Any laboratory abnormality considered 
to constitute an AE should be reported on the appropriate CRF. 
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE. Medical and scientific judgment should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an AE. 
Every effort must be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment.


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ASSESSING SEVERITY OF ADVERSE EVENTS
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate             Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see Serious 
Adverse Events and Other Events of Interest [Section 9.5.1.5] for the definition of an SAE).
ASSESSING RELATIONSHIP TO STUDY TREATMENT
Items to be considered when assessing the relationship of an AE to the study treatment are:
●
Temporal relationship of the onset of the event to the initiation of the study treatment
●
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
●
Whether the event is known to be associated with the study treatment or with other 
similar treatments
●
The presence of risk factors in the study subject known to increase the occurrence of the 
event
●
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
CLASSIFICATION OF CAUSALITY
Not Related
A causal relationship between the study treatment and the AE is not a reasonable 
possibility.
Related
A causal relationship between the study treatment and the AE is a reasonable 
possibility. The investigator must further qualify the degree of certainty as 
“possible” or “probable.”
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
●
Results in death
●
Is life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)
●
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Results in persistent or significant disability/incapacity


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●
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 
should also be considered SAEs. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication 
error. These events of interest are to be captured using the SAE procedures but are to be 
considered as SAEs only if they meet one of the above criteria. All AEs associated with events of 
interest are to be reported on the CRF whether or not they meet the criteria for SAEs.
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence associated with hospitalization.
●
Hospitalizations for respite care
●
Planned hospitalizations required by the protocol
●
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
●
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
●
Hospitalization for routine maintenance of a device (e.g., battery replacement)that was in 
place before study entry
CLINICAL LABORATORY DETERMINATIONS
Blood and urine samples will be collected for Clinical Laboratory Determinations at the 
Screening visit and at all subsequent clinic visit except Visit 2, 3 (Week 0, 4) (DB phase: Visit
4, 5, 6, 7 and early discontinuation and OLE phase; Visit 8, 9, 10 and early discontinuation). 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 1. Subjects should be in a seated or supine position during blood collection. 


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Table 1. Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), INR (only for patients taking warfarin)
Chemistry
Electrolytes
chloride, potassium, sodium 
Liver function tests
alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function parameters
blood urea/blood urea nitrogen, creatinine
Other
albumin, calcium, cholesterol, creatine kinase, globulin, glucose, 
lactate dehydrogenase, phosphorus, total protein, triglycerides, uric 
acid, HbA1c
Urinalysis
casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, 
protein, RBCs, specific gravity, WBCs
Others (only at Screening)
hepatitis B surface antigen, thyroid profile (TSH and free T4), 
vitamin B-12, folate
RBC = red blood cell, WBC = white blood cell, TSH = thyroid stimulating hormone
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Adverse Events and Other Events of Interest [Section 9.5.1.5]) and the CRF Completion 
Guidelines. In these instances, the AE corresponding to the laboratory abnormality will be 
recorded on the appropriate CRF.
For laboratory abnormalities meeting the criteria of SAEs (see Serious Adverse Events and Other 
Events of Interest [Sections 9.5.1.5]), the site must fax or email the SAE report including the 
laboratory report (as regionally required) to the sponsor using the SAE form (see Reporting of 
Serious Adverse Events [Section 9.5.4.1]).
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital signs (i.e., systolic and diastolic blood pressure (BP) [mmHg], pulse [beats per minute]), 
and weight [kg] will be obtained by a validated method at all clinic visits of DB and OLE phase
(Table 2 and Table 3). BP will be measured by a qualified instrument in the supine position (only 
at Screening and Visit 2 (Week 0)) and in the sitting position (at all visits). Automated 
measurement is available. All BP measurements should be performed on the same arm, 
preferably by the same person. Weight will be recorded. 
ELECTROCARDIOGRAMS
A 12-lead ECG will be performed at Screening and at the Visit 3, 4, 5, 6, 7 and early 
discontinuation of DB phase, and visit 8, 9 10 and early discontinuation of OLE phase. The ECG 


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will be a complete, standardized 12-lead recording. Electrocardiograms will be properly mounted 
and evaluated by the investigator or a qualified consultant.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see Adverse 
Events and Other Events of Interest [Section 9.5.1.5]) and the CRF Completion Guidelines. In 
these instances, the AE corresponding to the ECG abnormality will be recorded on the Adverse 
Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Serious Adverse Events and Other 
Events of Interest [Section 9.5.1.5]), the site must fax or email the SAE report including the ECG 
report to the sponsor using the SAE form (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
PREGNANCY TEST
Pregnancy test will be performed at all visits only for female subjects of childbearing potential
(pre-menopausal women or women who are amenorrhea for less than 12 months from the last 
menstrual cycle only). A serum β-hCG test will be performed at Screening, and urine test at all 
other visits.


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9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2. Schedule of Procedures/Assessments in Study E2020-K082-418:  <Core Study>
Phase
Screening
Double-Blind
Period
Screening
Baseline
Titration
Maintenance
Visit
1
2
3
4
5
6
7
Early 
Discontin
uation
Duration (Weeks)
Week 0
Week 4
Week 6 i)
Week 12
Week 18
Week 24
Duration (days)
-28 to -7
0
28-35
35-49
77-91
119-133
161-168
Informed Consent a)
X
Inclusion/Exclusion Criteria
X
X
Demography/Medical History
X
Diagnosis (NINDS-AIREN)
X
   Hachinski Ischemia Scale
X
   Neurological Examination
X
   Cranial MRI or CT b)
X
   CDR
X
Prior and Concomitant Medications
X
X
X
X
X
X
X
X
Randomization
X
Dispense Study Drug
X
X
X
X
X
Study Drug Compliance
X
X
X
X
X
X
Return Unused Study Medication
X
X
X
X
X
X
Efficacy
  MMSE c)
X
X
X
X
X
X
X
ADAS-cog c)
X
X
X
X
X
X
Executive function test c)
X
X
X
X
  CIBIC-plus
     CIBIS d)
X
     CIBIC d)
X
X
X
X
Safety
   Vital Signs e)
X
X
X
X
X
X
X
X
   12-lead ECG
X
X
X
X
X
X
X
   Clinical Laboratory Determinations f)
X
X
X
X
X
X
   Pregnancy Test (females only) g)
X
X
X
X
X
X
X
   Adverse Events h)
X
X
X
X
X
X
X
X


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a)
If the patient is unable to provide written informed consent, written consent must be obtained from the patient’s representative and 
verbal assent must be obtained from the patient. The caregiver must separately provide IC for his/her own participation in the 
study.
b) To be obtained as part of the Screening activities, if an MRI or CT was not obtained within the past 6 months. If obtained as part 
of Screening, a scan must be obtained at least 7 days prior to the baseline visit.
c) Every  test for one subject should administered by one rater throughout the core study (Baseline and DB phase).
d) CIBIS and every CIBIC for one subject should be evaluated by one rater throughout the study. Clinical information about the 
subject from any source can be used for the CIBIS, but not at any other time for the CIBIC during the study. The rater will refer to 
the CIBIS to complete the CIBIC.
e) Blood pressure, radial pulse, and Weight, all visits. 
f)
All clinical laboratory tests will include hematology, clinical chemistry and urinalysis. Additionally, at the Screening visit only, 
assessments of serum vitamin B12, folate levels, thyroid profile and hepatitis B and C titers will be obtained. INR only for patients
taking warfarin.
g) To perform only for pre-menopausal women or women who are amenorrhea for less than 12 months from the last menstrual cycle. 
Serum at Screening, urine at other visits.
h) Adverse events will be collected from the time subject signs informed consent form through the last visit. Serious adverse events 
will be collected through the last visit and for 30 days after study termination.
i) There should be an interval of 1 week or longer between Week 4 (Visit 3) and Week 6 (Visit 4).


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Table 3. Schedule of Procedures/Assessments in Study E2020-K082-418: <OLE phase>
Phase
Open-label extension
Period
Titration
Maintenance (Flexible dose)
Visit
7
8
9
10
Early 
Discontinuation
Duration (weeks of Core study)
Week 24
Duration (weeks of OLE phase)
Week 0
Week 6 o)
Week 12
Week 24
Duration (days of OLE phase)
28-42
77-91
161-175
Informed Consent  j)
X
Concomitant Medications
X
X
X
X
Dispense Donepezil
X
X
X
X
Donepezil Compliance
X
X
X
X
Return Unused Study Medication
X
X
X
X
Efficacy
     MMSE
X
X
X
X
Safety
    Vital Signs  k)
X
X
X
X
    12-lead ECG
X
X
X
X
    Clinical Laboratory Determinations l)
X
X
X
X
    Pregnancy Test (females only) m)
X
X
X
X
    Adverse Events  n)
X
X
X
X
j)  Subjects who completed the DB phase can be enrolled in this phase. Written informed consent must be obtained again.
k)  Blood pressure, radial pulse, and weight, all visits.
l)  All clinical laboratory tests will include hematology, clinical chemistry and urinalysis. INR only for patients taking warfarin.
m) To perform only for pre-menopausal women or women who are amenorrhea for less than 12 months from the last menstrual cycle.
n) Adverse events will be collected from the time subject signs informed consent form through the last visit. Serious adverse events 
will be collected through the last visit and for 30 days after study termination. 
o) The dose will be increased to 10 mg/day after confirmation of clinical response at Visit 8.


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9.5.2.2
Description of Procedures/Assessments Schedule
SCREENING PHASE ASSESSMENT SCHEDULE
SCREENING PERIOD ASSESSMENTS
Screening Visit (Visit 1, Day -28 to Day -7)
Written informed consent is obtained from the patients (if possible) and from legal 
guardian. The caregiver should separately provide written informed consent for his/her 
own participation in the study. Once informed consent has been obtained, the following 
procedures and evaluations will be performed:
●
Subject medical history; subject and caregiver demographic information
●
Record prior and concomitant medication use over the past 12-week.
●
Diagnosis (NINDS-AIREN): Hachinski Ischemia Scale, Neurological Examination, 
Cranial MRI or CT, CDR
●
MMSE (Mini-Mental State Examination)
●
Vital signs (systolic and diastolic BP in supine and sitting position, pulse), and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory assessments and pregnancy testing 
(serum, only females of childbearing potential)
●
Any AEs to be collected from the time of consent
●
Review of inclusion/exclusion criteria for subject and caregiver
●
Schedule Baseline Visit 2
BASELINE ASSESSMENTS
Baseline Visit (Visit 2, Week 0)
The results of all screening assessments and evaluations must be completed and reviewed 
by the PI before the subject’s arrival for the visit. Only those subjects who continue to 
meet all of the inclusion and none of the exclusion criteria are eligible to continue in the 
study. This is intended to minimize variability in subject and caregiver response. It is 
further recommended (whenever possible) that subjects be evaluated at approximately the 
same time of the day (e.g., morning or afternoon) at each subsequent visit.
The following procedures and evaluations will be performed:
●
Record all prior and concomitant medication use.
●
MMSE (Mini-Mental State Examination)
●
Vital signs (systolic and diastolic BP in supine and sitting position, pulse), and weight
●
Collect urine samples for pregnancy test (urine, only females of childbearing potential)
●
Record any AEs
●
Review of inclusion/exclusion criteria for subject and caregiver
●
ADAS-cog, executive function test
●
CIBIS


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●
Randomization (Randomly assigned as 1:1 ratio by IWRS system)
●
Dispense study medication. 
●
Schedule Visit3 
Caregiver’s Responsibilities: Prior to leaving the study site, the caregiver will receive an 
appointment schedule for the next visit and study medication containing drug supply 
sufficient for the period prior to the next clinic visit. It is the caregiver’s responsibility to 
help to ensure that the medication is stored safely in the home, to assist in patient 
compliance with taking their medication and making clinic visits and to provide the 
investigator with information for the evaluation of psychometric/neurological functions. 
DOUBLE-BLIND PHASE ASSESSMENT SCHEDULE
TITRATION PERIOD ASSESSMENTS
Visits 3 (Week 4, Day 28-35)
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
ADAS-cog
●
CIBIC
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-Lead ECG
●
Record any AEs
●
Dispense study medication. 
●
Schedule Visit 4
MAINTENANCE PERIOD ASSESSMENTS
Visits 4 (Week6, Day 35-49)
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-Lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for females of childbearing potential)
●
Record any AEs
●
Dispense study medication. 
●
Schedule Visit 5


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Visit 5 (Week12, Day 77-91)
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
ADAS-cog, executive function test
●
CIBIC
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)
●
Record any AEs
●
Dispense study medication. 
●
Schedule Visit 6
Visit 6 (Week 18, Day 119-133)
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
ADAS-cog
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)
●
Record any AEs
●
Dispense study medication
●
Schedule Visit 7
Visit 7 (Week 24, Day 161-168) or Early discontinuation
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
ADAS-cog, executive function test
●
CIBIC
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)


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●
Record any AEs
OPEN-LABEL EXTENSION PHASE ASSESSMENT SCHEDULE
BASELINE VISIT
Visit 7 (OLE Week 0, same as Week 24 of DB phase)
The following procedures and evaluations will be performed:
●
Obtain written informed consent
●
Dispense study medication. 
●
Schedule Visit 8 if the subjects will be enrolled in the open-label extension phase
●
TITRATION PERIOD ASSESSMENTS
Visit 8 (OLE Week 6, Day 28-42)
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)
●
Record any AEs
●
Dispense study medication. 
●
Schedule Visit 9
The dose can be increased to 10 mg/day after confirmation of clinical response at Visit 8
(Week 6). 
MAINTENANCE (FLEXIBLE DOSE) PERIOD ASSESSMENTS
Visit 9 (OLE Week 12, Day 77-91) 
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Collect unused study medication and record compliance
●
MMSE
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)
●
Record any AEs
●
Dispense study medication. 


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●
Schedule Visit 10
Visit 10 (OLE Week 24, Day 161-175) and Early discontinuation
The following procedures and evaluations will be performed:
●
Record all concomitant medication use
●
Retrieve unused study medication and record compliance
●
MMSE
●
Vital signs (sitting systolic and diastolic BP, pulse) and weight
●
12-lead ECG
●
Blood and urine samples for clinical laboratory determinations (including urine 
pregnancy test for all females of childbearing age)
●
Record any AEs
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of dementia 
associated with cardiovascular disease.
The safety assessments to be performed in this study, including hematology analysis, blood 
chemistry test, urinalysis, radiologic studies and assessments of AEs, are standard evaluations to 
ensure subjects safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 30 days after the subject’s last dose. All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to the 
study treatment should be reported to the sponsor regardless of the length of time that has passed 
since study completion.
Deaths and life-threatening events should be reported immediately by telephone. The 
immediate report should be followed up within 1 business day by emailing or faxing the 
completed SAE form.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.
For urgent safety issues call:  Designated CRO (C&R Research) contact number
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.


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It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt. If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or within 
30 days of last study treatment or any exposure to study drug through breastfeeding during study 
treatment or within 30 days of last study treatment must be reported 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File. The Pregnancy Report 
Form must be used for reporting. All pregnancies must be followed to outcome.  The outcome of 
the pregnancy must be reported as soon as possible but no later than 1 business day from the date 
the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Other Events of Interest
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE,
ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol. Overdose, 
misuse, abuse, and medication error are defined as follows: 
Overdose
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose 
Misuse
Intentional and inappropriate use of study drug not in accordance with the 
prescribed or authorized dose, route of administration, or indication(s) or use 
of prescription-only study drug without a prescription 


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Abuse
Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug use 
or subject harm while the study drug is in the control of site personnel or the 
subject.  
All AEs associated with an overdose should be captured on the Adverse Event CRF. Adverse 
events associated with overdose, misuse, abuse, or medication error should be reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1) even if the AEs do 
not meet serious criteria.  Abuse is always to be captured as an AE.  If the AE associated with an 
overdose, misuse, abuse, or medication error does not meet serious criteria, it must still be 
reported using the SAE form and in an expedited manner but should be noted as nonserious on 
the SAE form and the Adverse Event CRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within specific 
time frames).  For this reason, it is imperative that sites provide complete SAE information in the 
manner described above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for 
an individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the 
blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance. The 
format of these reports will be dictated by the local and regional requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated in 
the Schedule of Procedures/Assessments (Table 2 and Table 3).
The investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and provide appropriate medical treatment and other necessary measures for the 
subject.  A subject who has ceased to return for visits will be followed up by mail, phone, or 


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other means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.  This 
information will be recorded in the CRF.
Subjects who discontinue early from the study will be discontinued for one of these primary 
reasons: AE(s), lost to follow-up, subject choice, progression of disease, protocol violation, 
pregnancy, study terminated by sponsor, or other.  In addition to the primary reason, the subject 
may indicate one or more of secondary reasons for discontinuation.  Study disposition 
information will be collected on the appropriate CRF.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
Not applicable.
9.6
DATA QUALITY ASSURANCE
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.  Site audits will be made 
periodically by the sponsor’s or the CRO’s qualified compliance auditing team, which is an 
independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF. Completed, original CRFs are the sole property of Eisai and 
should not be made available in any form to third parties without written permission from Eisai, 
except for authorized representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (e.g., laboratory data), will be entered into a clinical system.
9.7
STATISTICAL METHODS
All statistical analyses will be performed by the sponsor or designee. Statistical analyses for DB 
phase will be performed after a snapshot of the database is obtained and released for unblinding. 


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Statistical analyses for OLE phase will be performed after the study is completed and the 
database is locked. 
9.7.1
Statistical and Analytical Plans
The statistical analyses of core study data (DB phase) are described in this section.  Further 
details of the analytical plan will be provided in the SAP, which will be finalized before database 
lock and treatment unblinding.
9.7.1.1
Study Endpoints
CO-PRIMARY ENDPOINT(S)
1) Cognitive function: Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-
cog)
Assessment of cognitive function measured by ADAS-cog from baseline to Week 24.
2) Global function: Clinicians Interview-Based Impression of Change-plus (CIBIC-plus)
Assessment of global function measured by CIBIC-plus at Week 24. 
SECONDARY ENDPOINT(S)
  1) Mini-Mental Status Examination (MMSE)   
Assessment of Mini-Mental Status Examination (MMSE) from baseline to Week 24
compared to placebo.
2) Executive function test (Trail making test (K-TMT-e))
Assessment of executive function test from baseline to Week 24 compared to placebo.
EXPLORATORY ENDPOINT(S)
Not applicable
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set (SAS) is the group of subjects who received at least one dose of study 
drug and had at least one postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least one dose 
of study drug and had at least one postdose primary efficacy measurement.
The Per Protocol Set (PPS) is the group of subjects who sufficiently complied with the protocol. 
Details of the evaluability criteria will be determined before database lock and treatment 
unblinding and will be specified in the Statistical Analysis Plan.


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9.7.1.3
Subject Disposition
The disposition of all subjects will be summarized. Subject disposition tables will include the number 
(percent) of subjects who will:
●
randomized into each treatment group;
●
included in each analysis populations (Safety, FAS, PPS);
●
discontinued from the study early, summarized by reason for discontinuation.
The number of subjects screened and the number (percent) who fail screening will also be 
summarized.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for each analysis set will be summarized for each 
treatment group and total of treatment groups using descriptive statistics (e.g., mean, SD, median, 
minimum, maximum and frequency, proportion). Continuous demographic and baseline 
variables include age, weight etc. Categorical variables include sex, age group etc.
9.7.1.5
Prior and Concomitant Therapy
Prior medication is defined as any medication taken prior to the first dose of study drug. 
Concomitant medication is defined as any medication taken during the treatment period between 
the date of the first dose of study drug and the date of the last dose of study drug, inclusive. 
Prior medications and concomitant medications will be summarized in number and percentages 
of subjects by Anatomical Therapeutic Chemical (ATC) Code by treatment group for all 
subjects.
9.7.1.6
Efficacy Analyses
The efficacy data observed from baseline to Week 24 will be used for analysis. All statistical 
tests will be conducted at the significance level of 5.0% (two-tailed).
The analysis will be conducted on the FAS and PPS, using the last observation carried forward 
(LOCF) method to impute missing data at Week 24, unless otherwise specified, and the observed 
cases (OC) populations at Week 24 and other time points. 
The analysis of FAS is primary, and that of PPS is a sensitivity analysis of FAS. 
CO-PRIMARY EFFICACY ANALYSIS
The co-primary efficacy variables are used as follows to determine whether donepezil has 
superior efficacy compared to placebo:
• For ADAS- cog change from baseline to Week 24, an analysis of covariance (ANCOVA) 
model with baseline as covariates and treatment as main effect will be used for testing 
main effect.
• For CIBIC-plus scores, least squares (LS) mean scores at Week 24 will be compared 
between groups to demonstrate numerical superiority of donepezil to placebo (the 


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difference is less than 0), using ANCOVA model with CIBIS-plus (covariate) and 
treatment group (main effect).
For the measurements of each visit and the change from baseline to each visit of both endpoints, 
descriptive statistics (median, mean, SD, minimum, maximum and number of patients with non-
missing data for both variables; number and percentages of each score for CIBIC-plus) will be 
presented. Where appropriate, least square (LS) mean, between-treatment difference in least 
square (LS) means, 95% confidence intervals (CIs) for the difference and p value in each visit 
will also be presented.
SECONDARY EFFICACY ANALYSES
MMSE and executive function test score change from Baseline to Week 24 will be analyzed 
using a same ANCOVA model as is described for the ADAS-cog. Other statistical inference 
(estimating and testing) will also be analyzed in the same way with primary analysis.
EXPLORATORY EFFICACY ANALYSES
Not applicable
9.7.1.7
Pharmacokinetic, 
Pharmacodynamic, 
and 
Pharmacogenomic/Pharmacogenetic 
Analyses
Not applicable
9.7.1.8
Safety Analyses
The evaluation of safety parameters will be conducted on the SAS. The incidence rates for AEs 
by body system, preferred term, severity, and relationship to study mediation will be calculated. 
Individual vital signs will be descriptively summarized by treatment group and total of treatment 
groups and visit. Changes from Baseline to each individual post- baseline visit and to the final 
visit will be calculated. For clinical laboratory parameters, changes from Baseline to each visit, 
will be summarized. Shift tables depicting shifts in or out of the normal range, from Baseline to 
the final study visit, will also be provided.
ECG data will be categorized at Baseline, and results for each subject at the end of treatment will 
be compared to those at Baseline. Data on other medications used by subjects during the study 
will be collected and summarized by therapeutic class and generic components.
EXTENT OF EXPOSURE
Study compliance and the extent of exposure to the study drug for the safety analysis set during 
the double-blind treatment period will be summarized descriptively.


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ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 15 or higher) lower level 
term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database.
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment, having 
been absent at pretreatment (Baseline) or 
●
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
●
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
Treatment-emergent AEs (TEAEs) will be summarized by treatment group.  The incidence of 
TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A 
subject will be counted only once within a SOC and PT, even if the subject experienced more 
than one TEAE within a specific SOC and PT.  The number (percentage) of subjects with 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (possibly related, probably related, and not related).
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5 Safety Assessments (Laboratory 
Measurements), the actual value and the change from baseline to each post-baseline visit and to 
the end of treatment (defined as the last on-treatment value) will be summarized by visit and 
treatment group using descriptive statistics(median, mean, SD, minimum, maximum and number 
of patients with non-missing data). Qualitative parameters listed in Section 9.5.1.5 will be 
summarized using frequencies (number and percentage of subjects), and changes from baseline 
to each post-baseline visit and to end of treatment will be reported using shift tables.  
Percentages will be based on the number of subjects with both non-missing baseline and relevant 
post-baseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during the 
treatment period.


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VITAL SIGNS
Descriptive statistics for vital signs parameters (i.e., systolic and diastolic blood pressure [BP] 
[mmHg], pulse [beats per minute], and weight (kg)) and changes from baseline will be presented 
by visit and treatment group. 
ELECTROCARDIOGRAMS
For ECG Measurement, Changes from Baseline or Screening to the last visit in the 12-lead ECG 
during the double-blind phase will be calculated by the incidence of a new or worsening 
clinically significant finding (treatment emergent ECG measures and physical examination shift 
table).
OTHER SAFETY ANALYSES
Not applicable.
9.7.1.9
Other Analyses
Not planned
9.7.1.10
Extension Phase Analyses
DEFINITIONS OF ANALYSIS SETS IN EXTENSION PHASE
The Safety Analysis Set of OLE-phase (SAS-OLE) is the subjects who received at least one dose 
of study drug and had at least one post dose safety assessment after starting OLE Phase. 
The Efficacy Analysis Set of OLE-phase (FAS-OLE) is the group of subjects who received at 
least one dose of study drug and had at least one post-dose MMSE measurement after starting 
Open-label Phase.    
EFFICACY ANALYSIS
For the efficacy endpoint, MMSE, descriptive statistics (median, mean, SD, minimum, 
maximum and number of patients with non-missing data) of the measurement and the change 
from week0 of extension phase to each visit will be presented by visit and total. 
SAFETY ANALYSIS
The same analysis method like the double-blind phase will be presented by total.
9.7.2
Determination of Sample Size
The primary endpoints are the change from baseline to Week 24 (LOCF) in ADAS-cog and the 
measurement at Week 24 (LOCF) of the CIBIC-plus.
The estimates of these endpoints were referred from the result of subgroup (MMSE less than 24) 
in pooled data of previous double blind studies (E2020-A001-307 and E2020-A001-308).


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The mean difference and standard deviation of the change from baseline to final visit in ADAS-
cog were estimated as -2.404±5.955, using pooled data of E2020 groups (5 mg+ 10 mg). When 
the significance level was set as 5.0% (two-tailed) and statistical power as 80.0%, the subject 
number needed to detect statistically significant difference by 2 sample t test was calculated to be 
196 (98/arm).
On the other hand, the mean difference and the standard deviation of CIBIC-plus score at the 
final visit were estimated as -0.261±1.162, when CIBIC-plus was regarded as continuous 
measurement [scored from 1 (marked improvement) to 7 (marked worsening) point]. The subject 
number needed to reduce the probability that donepezil is inferior to placebo in point estimate to 
2.5% or less, was calculated to be 308 (154/arm)..    
Therefore, the subjects number required to achieve primary objectives simultaneously became 
308 (154/arm). In consideration of exclusion from the analysis set (approximately 5%), the 
sample size was defined as 324 (162/arm).
9.7.3
Interim Analysis
Not applicable
9.7.4
Other Statistical/Analytical Issues
Not applicable
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistician determines that the analysis plan requires revision after the study begins, the 
person in charge of analysis and the study director will examine the validity of the revision and 
its influence on the objectives of the study, and determine if the revision can be implemented. 
The details of the revision will be described in the SAP and CSR for the study.


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10
REFERENCE LIST
Black RS, Barclay LL, Nolan KA, Thaler HT, Hardiman ST and Blass JP. Pentoxifylline in 
cerebrovascular dementia.  J Am Geriatric Soc. 1992;40:237-244.
De la Torre JC. Alzheimer disease as a vascular disorder.  Stroke. 2002;33:1152-1162.
Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S and Damaraju CV. Efficacy of 
galantamine in probable vascular dementia and Alzheimer’s disease combined with 
cerebrovascular disease: A randomized trial.  Lancet. 2002;359:1283-1290.
Folstein MF, Folstein SE and McHugh PR.  Mini-mental state: A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-198.
Geldmacher DS and Whitehouse PJ.  Evaluation of dementia.  NEJM.  1996;335:330-336.
Holmes C, Cairns N, Lantos P and Mann A. Validity of current clinical criteria for Alzheimer’s 
disease, vascular dementia and dementia with Lewy bodies.  Br J Psychiatry. 1999:174:45-50.
Kalaria RN and Ballard C. Overlap between pathology of Alzheimer disease and vascular 
dementia.  Alzheimer Dis Assoc Disord. 1999;13:S115-123.
Kalaria RN and Roman GC. Evidence for a cholinergic deficit in vascular dementia. Manuscript 
in preparation.
Kittner B, De Deyn PP and Erkinjuntti T.  Investigating the natural course and treatment of 
vascular dementia and Alzheimer’s disease.  Parallel study populations in two randomized, 
placebo-controlled trials.  Ann NY Acad Sci. 2000;903:535-541.
Lopez OL, Larumbe MR, Becker JT, Rezek D, Rosen J, Klunk W and DeKosky ST. Reliability 
of NINDS-AIREN criteria for the diagnosis of vascular dementia.  Neurol. 1994;44:1240-1245.
Marcusson J, Rother M, Kittner B, Rossner M, Smith RJ, Babic T, Folnegovic-Smalc V, Moller 
HJ and Labs KH. A 12-month, randomized, placebo-controlled trial of propentofylline 
(HWA285) in patients with dementia according to DSM-IIIR. Dementia Geriatric and Cognitive 
Disorders. 1997;8:320-328.
McKhann G, Drachman D, Folstein M, Katzman R, Price D and Stadlan EM.  Clinical diagnosis 
of Alzheimer’s disease.  Report of the NINCDS-ADRDA work group under the auspices of the 
Department of Health and Human Services Task force on Alzheimer’s Disease.  Neurol. 
1984;34:939-944.


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Nyenhuis DL and Gorelick PB. Vascular dementia: A contemporary review of epidemiology, 
diagnosis, prevention and treatment.  J Am Geriatric Soc. 1998;46:1437-1448. 
Pantoni L, Bianchi C, Beneke M, Inzitari D, Wallin A and Erkinjuntti T. The Scandinavian 
multi-infarct dementia trial: a double-blind, placebo-controlled trial on nimodipine in multi-
infarct dementia.  J Neurol Sci. 2000;175: 116-123.
Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, 
Orgogozo JM, Brun A and Hofman A. Vascular dementia: Diagnostic criteria for research 
studies.  Report of the NINDS-AIRENS International workshop.  Neurol. 1993;43:250-260.
Swanwick GR, Coen RF, Lawlor BA, O'Mahony D, Walsh JB and Coakley D. Utility of 
ischemic scores in the differential diagnosis of Alzheimer’s disease and ischemic vascular 
dementia. Int Psychogeriatr. 1996;8(3):413-424.
Wetterling T, Kanitz R-D and Borgis K-J. Comparison of different diagnostic criteria for 
vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN).  Stroke. 1996;27(1):30-36.


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11
PROCEDURES 
AND 
INSTRUCTIONS 
(ADMINISTRATIVE 
PROCEDURES)
11.1 CHANGES TO THE PROTOCOL
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the sponsor before implementation.  Amendments specifically affecting the 
safety of subjects, the scope of the investigation, or the scientific quality of the study require 
submission to health or regulatory authorities as well as additional approval by the applicable 
IRBs/IECs.  These requirements should in no way prevent any immediate action from being 
taken by the investigator, or by the sponsor, in the interest of preserving the safety of all subjects 
included in the study.  If the investigator determines that an immediate change to or deviation 
from the protocol is necessary for safety reasons to eliminate an immediate hazard to the 
subjects, the sponsor’s medical monitor and the IRB/IEC for the site must be notified 
immediately.  The sponsor must notify the health or regulatory authority as required per local 
regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local regulations.  
In these cases, the sponsor may be required to send a letter to the IRB/IEC and the Competent 
Authorities detailing such changes.
11.2 ADHERENCE TO THE PROTOCOL
The investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5 and KGCP).
11.3 MONITORING PROCEDURES
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be conducted 
by the assigned CRA as described in the monitoring plan.  The investigator will allow the CRA 
to inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCP and 
local regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the local 
auditing agency and IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following:
●
Clinic, office, or hospital charts
●
Copies or transcribed health care provider notes which have been certified for accuracy 
after production


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●
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (e.g., sonograms, CT scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of 
how these images are stored, including microfiche and photographic negatives
●
Pain, quality of life, or medical history questionnaires completed by subjects
●
Records of telephone contacts
●
Diaries or evaluation checklists
●
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
●
Laboratory results and other laboratory test outputs (e.g., urine pregnancy test result 
documentation and urine dip-sticks)
●
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
●
CRF components (e.g., questionnaires) that are completed directly by subjects and serve 
as their own source
11.4 RECORDING OF DATA
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except when a 
section of the CRF itself is used as the source document.  Any correction to entries made on the 
CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correct is identified, the reason for the change is stated, and the original data are not 
obscured.  Only data required by the protocol for the purposes of the study should be collected.
This study will use electronic CRF system. The investigator must sign by electronic signature on 
each CRF.
11.5 IDENTIFICATION OF SOURCE DATA
ICH GCP guidelines specifically acknowledge that data may in some cases be recorded directly 
on CRFs. According to ICH guidance, if sections of the CRF are to be considered source 
documents, these sections or pages should be identified in the protocol before study inception.
All data to be recorded on the CRF must reflect the corresponding source documents. For the 
following item(s), the data recorded directly on the CRF are to be considered source data:
●
(Using bullet format, add items to be recorded on the CRF that will be considered source 
data, e.g., reasons for discontinuation of study treatment, comments and other 
information on AEs [severity, relationship to study drug, outcome, etc.], reasons for dose 
modification, indication for prior/concomitant medication, sampling times for drug 
concentrations, sampling times for clinical laboratory tests.)


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11.6 RETENTION OF RECORDS
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents, including but not limited to the protocol, copies of 
CRFs, the Investigator's Brochure, and regulatory agency registration documents (e.g., ICFs, and 
IRB/IEC correspondence).  In addition, the sponsor will send a list of treatment codes by study 
subject to the investigator after the clinical database for this study has been locked. It is 
mandatory to keep the clinical related documents at least for 3 years from this clinical trial 
completion or termination.  
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records.
11.7 AUDITING PROCEDURES AND INSPECTION
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately.
11.8 HANDLING OF STUDY DRUG
All study drugs will be supplied to the principal investigator (or a designated pharmacist) by the 
sponsor. Drug supplies must be kept in an appropriate secure area (e.g., locked cabinet) and 
stored according to the conditions specified on the drug labels.  The investigator (or a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study drug 
in a drug accountability ledger, a copy of which must be given to the sponsor at the end of the 
study.  An accurate record of the date and amount of study drug dispensed to each subject must 
be available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has been 
received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.
11.9 PUBLICATION OF RESULTS
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant to 


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the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 DISCLOSURE AND CONFIDENTIALITY
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and will not be 
disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the sponsor.  No data collected as part of 
this study will be used in any written work, including publications, without the written consent of 
the sponsor.  These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
executed between the sponsor/CRO and the institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 DISCONTINUATION OF STUDY
The sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a study is prematurely terminated or suspended, the sponsor will promptly inform 
the investigators/institutions and regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the investigator terminates or suspends a study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the sponsor and the IRB/IEC and provide the sponsor and the IRB/IEC 
with a detailed written explanation of the termination or suspension.  Study records must be 
retained as noted above.
11.12 SUBJECT INSURANCE AND INDEMNITY
The sponsor will provide insurance for any subjects participating in the study in accordance with 
all applicable laws and regulations.


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APPENDICES
APPENDIX I.
NINDS-AIREN CRITERIA FOR THE DIAGNOSIS OF VASCULAR DEMENTIA
PAGE 1 OF 4
Reference:
Roman, G.C.; Tatemichi, T.K.; Erkinjuntti, T.; et al.  Vascular dementia:  
Diagnostic criteria for research studies.  Report of the NINDS-AIREN 
International Workshop.  Neurology 43: 250-260 (1993).
The diagnosis of dementia associated with cerebrovascular disease (VaD) can be easily made in 
patients with a clear history of strokes and cognitive impairment when there is an obvious 
temporal connection.  However, the diagnosis can be difficult to establish if cerebrovascular 
disease alone is the cause for dementia or if it is merely a contributory or coincidental finding.  
To assist in determining causation, various criteria have been proposed to establish the diagnosis.  
The criteria for probable ischemic vascular dementia for research studies as determined by an 
international consortium (NINDS-AIREN) presented below.  
NINDS-AIREN Criteria for Ischemic Vascular Dementia
Essential Requirements:
1) Dementia involving memory failure and other cognitive functions (not a circumscribed 
neurobehavioral deficit) interfering with function in daily living
2) Cerebrovascular disease as documented by a combination of history, examination and/or 
brain imaging.
3) Evidence that 1 and 2 are related;  features that support causality include:
Temporal relationship between stroke and dementia
Abrupt or stepwise deterioration in mental function or a fluctuating course
Specific brain imaging findings indicating damage to regions important for higher cerebral 
function.


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APPENDIX I
NINDS-AIREN CRITERIA FOR THE DIAGNOSIS OF VASCULAR DEMENTIA
PAGE 2 OF 4
Supportive Clinical Features
History of cerebrovascular risk factors (e.g., hypertension, diabetes mellitus, cardiac 
disease, hypercholesterolemia, smoking)
Early appearance of gait disturbance or frequent falls.
Early appearance of urinary incontinence not explained by urological disease
Frontal lobe or extrapyramidal features
Pseudobulbar features with or without emotional incontinence (pathological crying)
Diagnostic specificity for the NINDS-AIREN criteria have not been validated in large scale 
studies.  The NINDS-AIREN criteria have a high specificity but low sensitivity for the diagnosis 
of probable vascular dementia.  Physical impairment complicates evaluation of dementia and 
may introduce a bias against evaluation of agents which may potentially improve cognitive 
function.  
Criteria for the Diagnosis of Probable Vascular Dementia:
1) Dementia: 
Defined by a cognitive decline from a previously higher functioning and manifest by 
impairment of memory and two or more cognitive domains (orientation, attention, 
language, visuospatial functions, executive functions, motor control and praxis), 
preferably established by clinical examination and documented by neuropsychological 
testing; deficits should be severe enough to interfere with activities of daily living not due 
to the physical effects of stroke alone.
Exclusion Criteria:  disturbance of consciousness, delirium, psychosis, severe aphasia, 
major sensorimotor impairment precluding neuropsychological testing.  Systemic 
disorders or other brain diseases (including AD) that in and of themselves could account 
for deficits in memory and cognition.


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APPENDIX I
NINDS-AIREN CRITERIA FOR THE DIAGNOSIS OF VASCULAR DEMENTIA
PAGE 3 OF 4
2) Cerebrovascular Disease:
Defined by the presence of focal signs on neurologic examination, such as hemiparesis, 
lower facial weakness, Babinski sign, sensory deficit, hemianopia, and dysarthria 
consistent with stroke (with or without a history of stroke), and evidence for relevant 
cerebrovascular disease (CVD) by brain imaging (CT or MRI) including multiple large 
vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal 
forebrain or anterior or posterior cerebral artery distribution), as well as multiple basal 
ganglia and white matter lacune or extensive perivascular white matter lesions or 
combinations.
3) A relationship between 1 and 2 above
Manifest or inferred by the presence of one or more of the following:
A) Onset of dementia within 3 months of a recognized stroke.
B) Abrupt deterioration in cognitive functions, or
C) Fluctuating stepwise progression of cognitive deficits.
Clinical features consistent with the diagnosis of probable vascular dementia include the 
following:
A) Early presence of a gait disturbance (small step gait or marche a petit pas, or magnetic 
apraxic-ataxic or parkinsonian gait); 
B) History of unsteadiness and frequent unprovoked falls;
C) Early urinary frequency, urgency and other symptoms not explained by urologic 
disease;
D) Pseudobulbar palsy
E) Personality and mood changes, abulia, depression, emotional incontinence or other 
subcortical deficits including psychomotor retardation and abnormal executive 
function.


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APPENDIX I
NINDS-AIREN CRITERIA FOR THE DIAGNOSIS OF VASCULAR DEMENTIA
PAGE 4 OF 4
Criteria for the Diagnosis of Possible Vascular Dementia:
Dementia as defined in section 1 above with focal neurologic signs in patients in whom brain 
imaging studies fail to confirm the presence of definite cerebrovascular disease as defined in 
Section 2 above; or the absence of a clear temporal relationship between dementia and stroke; or 
in patients with the subtle onset and variable course (plateau or improvement) of cognitive 
deficits and evidence for relevant cerebrovascular disease.
Criteria for the Diagnosis of Definite Vascular Dementia:
1) Clinical criteria for probable vascular dementia as described in section 1-3 above, and
2) Histopathologic evidence of cerebrovascular disease obtained from biopsy or autopsy
3) Absence of neurofibrillary tangles or neuritic plaques exceeding those expected for age
4) Absence of other clinical or pathologic disorders capable of producing dementia.
Criteria for the Diagnosis of Alzheimer’s disease with Cerebrovascular disease:
1) Patients fulfill the clinical criteria for the diagnosis of Alzheimer’s disease 
2) Patients present clinical or brain imaging evidence for Cerebrovascular disease.


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APPENDIX II.
CONCOMITANT MEDICATIONS
A.
Concomitant Medications Not Allowed During the Study
The following medications are NOT ALLOWED as concomitant medications during the study.  
This list is not exhaustive and, therefore, the Investigator is asked to contact sponsor’s Medical 
Monitor or CRO for clarification regarding the acceptability of other agents.
1) Prohibited concomitant medications
Anti-dementia drugs
donepezil(except for study drug)
galantamine
rivastigmine
memantine
Choline stimulants (cholinesterase inhibitor, choline agonists, except for topical agents)
bethanechol
pilocarpine
carbachol
pyridostigmine
neostigmine
Antiparkinsonian drugs
amantadine 
benserazide/levodopa
benztropine 
biperiden
bromocriptine 
dihydroergocryptine
Entacapone
levodopa/carbidopa
pramipexole
procyclidine
ropinirole
rotigotine
selegiline
trihexyphenidyl
Tricyclic antidepressants
amitriptyline 
amoxapine
clomipramine 
dothiepin 
imipramine
mirtazapine
nortriptyline
quinupramine
Antipsychotics
amisulpride
nemonapride
aripiprazole
olanzapine
blonanserin
paliperidone palmitate
bromperidol
perphenazine
chlorpromazine 
pimozide
clozapine
quetiapine
escitalopram oxalate
risperidone
haloperidol
sulpiride
levomepromazine
ziprasidone 
molindone 
zotepine


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Hypnotics 
chloral 
flurazepam 
chlordiazepoxide 
midazolam
dexmedetomidine 
nimodipine
diphenhydramine 
phenobarbital 
doxylamine
Triazolam
flunitrazepam
Nootropics & Neurotonics
acetyl-L-carnitine
oxiracetam
choline alfoscerate
piracetam
citicoline
protirelin
nimodipine
Gingko biloba
2) Restricted concomitant medications (The dose should be maintained)
Antidepressants
bupropion 
moclobemide
citalopram 
paroxetine 
duloxetine
sertraline 
escitalopram 
tianeptine 
fluoxetine 
trazodone 
fluvoxamine 
venlafaxine 
lithium 
Hypericum
mianserin 
hyperici 
milnacipran 
Anxiolytics
alprazolam
ethyl loflazepate
bromazepam
etizolam
buspirone
hydroxyzine 
clobazam
lorazepam
clorazepate dipotassium
mexazolam
clotiazepam
tandospirone 
diazepam
tofisopam
Hypnotics (only short acting)
zolpidem
brotizolam
lormetazepam
rilmazafone
zopiclone
ramelteon


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6 July 2017 / v2.2
Confidential
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APPENDIX III.
SPONSOR’S GRADING FOR LABORATORY VALUES
The table below is an example of the Sponsor’s Grading Laboratory Values based on Common 
Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 
(v4.03: June 14, 2010).  The study team should assess whether the Sponsor’s Grading for 
Laboratory Values is appropriate for individual studies.  If this appendix is used, it is the study 
team’s responsibility to ensure that the current version of the Sponsor’s Grading Laboratory 
Values is placed in the appendix.
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
< LLN – 10.0 g/dL
< LLN – 100 g/L
< LLN – 6.2 mmol/L
< 10.0 – 8.0 g/dL
< 100 – 80 g/L
< 6.2 – 4.9 mmol/L 
< 8.0 g/dL
< 80 g/L
< 4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
< LLN – 3.0 x 109/L
< LLN – 3000/mm3
< 3.0 – 2.0 x 109/L
< 3000 – 2000/mm3
< 2.0 – 1.0 x 109/L
< 2000 – 1000/mm3
< 1.0 x 109/L
< 1000/mm3 
Lymphocytes 
< LLN – 800/mm3 
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L
Neutrophils 
< LLN – 1.5 x 109/L
< LLN – 1500/mm3
< 1.5 – 1.0 x 109/L
< 1500 – 1000/mm3
< 1.0 – 0.5 x 109/L
< 1000 – 500/mm3 
< 0.5 x 109/L
< 500/mm3 
Platelets
< LLN – 75.0 x 109/L
< LLN – 75,000/mm3
< 75.0 – 50.0 x 109/L
< 75,000 – 50,000/mm3
< 50.0 – 25.0 x 109/L
< 50,000 – 25,000/mm3
< 25.0 x 109/L
< 25,000/mm3
METABOLIC/LABORATORY
Albumin, 
serum-
low 
(hypoalbuminemia) 
< LLN – 3 g/dL
< LLN – 30 g/L
< 3 – 2 g/dL
< 30 – 20 g/L
< 2 g/dL
< 20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
ALT
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
AST
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Bicarbonate, serum-low 
< LLN – 16 mmol/L
< 16 – 11 mmol/L
<11 – 8 mmol/L
< 8 mmol/L 
Bilirubin (hyperbilirubinemia)
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN
> 3.0 – 10.0 x ULN 
> 10.0 x ULN
Calcium, serum-low (hypocalcemia) 
< LLN – 8.0 mg/dL
< LLN – 2.0 mmol/L
< 8.0 – 7.0 mg/dL
< 2.0 – 1.75 mmol/L
< 7.0 – 6.0 mg/dL
< 1.75 – 1.5 mmol/L
< 6.0 mg/dL
< 1.5 mmol/L


Eisai Co., Ltd.
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6 July 2017 / v2.2
Confidential
Page 71 of 74
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
> ULN – 11.5 mg/dL
> ULN – 2.9 mmol/L
> 11.5 – 12.5 mg/dL
> 2.9 – 3.1 mmol/L
> 12.5 – 13.5 mg/dL
> 3.1 – 3.4 mmol/L
> 13.5 mg/dL
> 3.4 mmol/L
Cholesterol, 
serum-high 
(hypercholesterolemia)
> ULN – 300 mg/dL
> ULN – 7.75 mmol/L 
> 300 – 400 mg/dL
> 7.75 – 10.34 mmol/L 
> 400 – 500 mg/dL
> 10.34 – 12.92 mmol/L 
> 500 mg/dL
> 12.92 mmol/L 
Creatinine
> ULN – 1.5 x ULN
> 1.5 – 3.0 x ULN
> 3.0 – 6.0 x ULN
> 6.0 x ULN
GGT (γ-Glutamyl transpeptidase) 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
> ULN – 160 mg/dL
> ULN – 8.9 mmol/L 
Fasting glucose value:
> 160 – 250 mg/dL
> 8.9 – 13.9 mmol/L 
> 250 – 500 mg/dL;
> 13.9 – 27.8 mmol/L;
hospitalization indicated
> 500 mg/dL;
> 27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
< LLN – 55 mg/dL
< LLN – 3.0 mmol/L
< 55 – 40 mg/dL
< 3.0 – 2.2 mmol/L
< 40 – 30 mg/dL
< 2.2 – 1.7 mmol/L
< 30 mg/dL
< 1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, 
serum-low 
(hypophosphatemia) 
< LLN – 2.5 mg/dL
< LLN – 0.8 mmol/L
< 2.5 – 2.0 mg/dL
< 0.8 – 0.6 mmol/L
< 2.0 – 1.0 mg/dL
< 0.6 – 0.3 mmol/L
< 1.0 mg/dL
< 0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
> ULN – 5.5 mmol/L 
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L
hospitalization indicated
> 7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
< LLN – 3.0 mmol/L
< LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
< 3.0 – 2.5 mmol/L
hospitalization indicated
< 2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
> ULN – 150 mmol/L
> 150 – 155 mmol/L
> 155 – 160 mmol/L
hospitalization indicated
> 160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
< LLN – 130 mmol/L
N/A
< 130 – 120 mmol/L
< 120 mmol/L
life-threatening 
consequences
Triglyceride, 
serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
> 300 – 500 mg/dL
> 3.42 – 5.7 mmol/L 
> 500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
> 1000 mg/dL
> 11.4 mmol/L
life-threatening 
consequences 


Eisai Co., Ltd.
E2020-K082-418
6 July 2017 / v2.2
Confidential
Page 72 of 74
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high (hyperuricemia)
> ULN – 10 mg/dL 
≤ 0.59 mmol/L without 
physiologic 
consequences 
N/A
> ULN –
10 mg/dL 
≤0.59 
mmol/L 
with 
physiologic 
consequences 
> 10 mg/dL
> 0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).


Eisai Co., Ltd.
E2020-K082-418
6 July 2017 / v2.2
Confidential
Page 73 of 74
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2020-K082-418
Study Protocol Title:
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study of Donepezil Hydrochloride (E2020) in Patients 
with Dementia Associated with Cerebrovascular Disease
Investigational Product 
Name:
E2020 donepezil HCl (Aricept)
SIGNATURE
Sponsor:
Eisai Co., Ltd.
Date
PPD
PPD


Eisai Co., Ltd.
E2020-K082-418
6 July 2017 / v2.2
Confidential
Page 74 of 74
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2020-K082-418
Study Protocol Title:
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study of Donepezil Hydrochloride (E2020) in 
Patients with Dementia Associated with Cerebrovascular Disease
Investigational Product 
Name:
E2020 donepezil HCl (Aricept)
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date


Protocol No.: E2020-K082-418
1 / 1
Protocol Amendment Comparison Table: from v2.1 (5 Apr 2013) to v2.2 (6 July 2017)
No
Page 
No
Content
Detail Content
Before (V2.1, 5 Apr 2013)
After (V2.2, 6 July 2017)
Remark
1
1 
page
1. Title
Approval Date
V2.1, 5 Apr 2013
V2.2, 6 July 2017
Version update
2
3 
page
2. Clinical Protocol 
Synopsis
Study Period and 
Phase of 
Development
From June 2013 to December 2017, Phase 4
From June 2013 to January 2019, Phase 4
Study period Extension
(Extension of due date for CSR
submission was approved by 
MFDS)

SAP_001.pdf: 
PPD


PPD


PPD




















































PPD