Conditions: Dementia With Lewy Bodies
Keywords: Irsenontrine Montreal Cognitive Assessment Neuropsychiatric Inventory Mini-Mental State Examination Cognitive Fluctuation Inventory
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 326
Healthy volunteers: no

Brief summary:
This study will be conducted to compare Irsenontrine to placebo on the cognitive endpoint of Montreal Cognitive Assessment (MoCA) and the global clinical endpoint of Clinician's Interview Based Impression of Change Plus (CIBIC-Plus) Caregiver Input in participants with dementia with Lewy bodies after 12 weeks of treatment.

Detailed description:

Arms:
arm 1: Participants will be randomized to receive a 50 milligram (mg) once daily oral dose of Irsenontrine for 12 weeks. arm 2: Participants will be randomized to receive a 50 mg once daily oral dose of Irsenontrine-matched placebo for 12 weeks.

Interventions: intervention 1: Irsenontrine intervention 2: Placebo
Intervention descriptions: intervention 1: Oral hypromellose capsules. intervention 2: Oral hypromellose capsules.

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol
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REVISION HISTORY
Revisions to Version 5.0
New version/date:  Version 6.0/03 Jan 2020 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Added results of 
nonclinical toxicology 
study.
New nonclinical toxicology 
findings
Section 7.1.1.3
Section 7.2.2
Added requirement for 
males subjects to use 
highly effective 
contraception and 
requirement to report 
pregnancy in female 
partners of male 
subjects.
New nonclinical toxicology 
findings
Section 9.4.7.3
Section 9.5.4.2
Section 9.5.5
Revised the order of the 
secondary efficacy 
endpoints.
To enable the secondary 
endpoints to be part of the 
statistical hierarchy of testing 
so that this study can be used 
in the NDA as one of the 
pivotal studies
Synopsis

Objectives

Study Endpoints
Section 8.2
Section 9.7.1.1.2
Revisions to Version 4.0
New version/date:  Version 5.0/03 Sep 2019 (per Amendment 04)
Change
Rationale
Affected Protocol Sections
Specified the percentage
of randomized subjects 
who will be on 
memantine.
To comply with the EU 
Voluntary Harmonisation 
Procedure requirement for 
approval
Synopsis

Study Design
Section 7.2.1
Section 9.1


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Revisions to Version 3.0
New version/date:  Version 4.0/10 Jul 2019 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Removed restriction 
on the use of 
memantine prior to 
and during study 
participation.
Use of memantine is 
increasingly more common in 
patients with dementia with 
Lewy bodies (DLB) based on 
ongoing surveys with 
investigators, and it is also 
explicitly cited in some national 
treatment guidelines for DLB 
(eg, UK National Institute for 
Health and Care Excellence
[2018]).
Synopsis

Study Design

Inclusion Criteria

Concomitant Drug/Therapy

Statistical Methods –
Efficacy Analyses
Section 7.1.1
Section 7.2.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.7.2
Section 9.5.1.2.1
Section 9.5.5
Section 9.7.1.4
Section 9.7.1.6.1
Section 9.7.1.8.2
Section 10
Removed ad hoc 
futility analysis
This was always considered 
optional and only to be 
performed if necessary.  
Moreover, ongoing review of 
variability data in the efficacy 
endpoints indicated that such a 
futility analysis would have 
high risk of a false negative 
conclusion on efficacy. 
Therefore, it will not be 
conducted.
Synopsis

Interim Analyses
Section 9.7.3
Increased number of 
sites from 60 to 70
Due to the screen failure rate 
being higher than expected and 
some sites having exhausted 
their pool of subjects for 
enrollment, more new sites, to 
replace sites planned for closure 
are required.
Synopsis

Sites
Section 6
Section 9.3


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Revisions to Version 2.0
New version/date:  Version 3.0/15 Jun 2018 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Specified secondary 
endpoints for safety and 
tolerability
To specify measurable
endpoints for safety and 
tolerability

Synopsis:

Secondary 
Endpoints

Section 9.7.1.1.2
Add Section headings 
7.2.1 and 7.2.2
7.2.1: Correction for 
clarity
7.2.2: To add Risk-
Benefit Summary for 
completeness

Section 7.2.1

Section 7.2.2
Updated information 
regarding breaking of 
blind
Correction

Section 9.4.6
Added “Capacity Rule”
To comply with 
feedback from Health 
Authorities

Synopsis

Inclusion criteria

Section 5.3

Section 9.3.1

Section 9.5.5
Updated 
completion/discontinuation 
information
To add safety criteria

Section 9.5.5
Added cerebrospinal fluid 
(CSF) substudy criteria 
and description
To provide all 
procedures specific for 
the optional CSF 
substudy in one 
location in the protocol 

Appendix 4


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Revisions to Version 1.0
New version/date:  Version 2.0/30 Mar 2018 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Additional specification for 
implementation of  Inclusion 
Criterion 2
Restricts enrollment to 
subjects who do not need 
new nuclear scan in 
countries where additional 
central regulatory review of 
radiation exposure is 
required. When such 
approval is granted, 
enrollment restriction is 
removed.
Synopsis, Inclusion Criteria
Section 9.3.1
Updated estimated blood 
volume collected during the 
study  
Alignment with Schedule 
of Procedures
Section 9.5.2.2, Table 7
Heart rate was changed to 
pulse when describing vital 
signs
Company convention
Section 9.5.1.5.5
Updated Movement 
Disorders Society Unified 
Parkinson’s Disease Rating 
Scale (MDS-UPDRS) to 
include number of items, 
categories, and correct 
scoring
Correction
Synopsis, Safety 
Assessments
Section 9.5.1.5.8
Specified time for vital signs 
to align with approximate 
tmax time window at specific 
visits
As recommended by 
Japanese PMDA
Section 9.5.2.1, Table 6
Recommended subjects to 
avoid prolonged exposure to 
the sun or exposure to 
artificial ultra-violet light
As recommended by 
Japanese PMDA
Section 9.4.7.3
Removed criterion for pulse 
increase in the definition of 
orthostatic hypotension
As recommended by 
Japanese PMDA and for 
consistency with the 
literature
Section 9.5.1.5.5


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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2027-G000-201
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Study 
To Evaluate the Efficacy, Safety and Tolerability of E2027 in Subjects With
Dementia With Lewy Bodies
Sponsor:  
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd.  
European Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd.  
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
JP
Investigational 
Product Name:
E2027
Indication:
Subjects with dementia with Lewy bodies
Phase:
2
Approval Date:  
V1.0
29 Jan 2018 (original protocol)
V2.0
30 Mar 2018 (Amendment 01)
V3.0
15 Jun 2018 (Amendment 02)
V4.0
10 Jul 2019 (Amendment 03)
V5.0
03 Sep 2019 (Amendment 04)
V6.0
03 Jan 2020 (Amendment 05)
IND Number:
123614
EudraCT Number:
2017-003728-64
GCP Statement:
This study is to be performed in full compliance with International Council 
for 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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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2027
Name of Active Ingredient:  7-(2-Methoxy-3,5-dimethylpyridin-4-yl)-1-[(3S)-tetrahydrofuran-3-
yl]-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one maleate (International Union of Pure and Applied 
Chemistry [IUPAC])
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Study To Evaluate the Efficacy, 
Safety and Tolerability of E2027 in Subjects With Dementia With Lewy Bodies
Investigators
Investigators in North America, Europe and Japan
Sites
Approximately 70 sites in North America, Europe, and Japan (revised per Amendment 03)
Study Period and Phase of Development
Approximately 22 weeks for each subject.
Approximately 20 months for the study.
Phase 2
Objectives
Primary Objectives

To determine whether E2027 is superior to placebo on the cognitive endpoint of Montreal 
Cognitive Assessment (MoCA) in subjects with dementia with Lewy bodies (DLB) after 
12 weeks of treatment

To determine whether E2027 is superior to placebo on the global clinical endpoint of Clinician’s 
Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) after 12 weeks of 
treatment
Secondary Objectives
(Order revised per Amendment 05)

To determine whether E2027 is superior to placebo on the following secondary endpoints after 
12 weeks of treatment:
-
Clinician Global Impression of Change in Dementia with Lewy Bodies (CGIC-DLB)
-
Cognitive Fluctuation Inventory (CFI)
-
Mini-Mental State Examination (MMSE)
-
Neuropsychiatric Inventory (NPI)

To evaluate the safety and tolerability of E2027 in subjects with DLB

To characterize the population pharmacokinetics (PPK) of E2027 in subjects with DLB,
including evaluation of the effects of intrinsic and extrinsic factors on E2027 pharmacokinetics 
(PK)


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Exploratory Objectives

To explore the efficacy of E2027 compared to placebo on the following endpoints after 12 weeks 
of treatment:
-
Scales for Outcome in Parkinson’s disease-Sleep (SCOPA-Sleep)
-
Dementia-related quality of life as assessed by the Dementia Quality of Life Measure 
(DEMQOL; interview of subject) and Dementia Quality of Life Measure by Proxy 
(DEMQOL-Proxy; interview of caregiver or informant about subject)
-
General health status as assessed by the EuroQol- 5 Dimension questionnaire (EQ-5D; 
completed by subject) and EuroQol- 5 Dimensions questionnaire by Proxy Version 1 
(EQ-5D Proxy; caregiver or informant completion of report about subject)

To evaluate the relationship between PK exposure of E2027 and its effects on various efficacy 
and safety endpoints

To explore the PK/pharmacodynamic (PD) relationship between the exposure of E2027 in 
cerebrospinal fluid (CSF)/plasma and its effects on CSF PD biomarker endpoints, including CSF 
cyclic guanosine monophosphate (cGMP), if data permit

To explore the relationship between the E2027 PD effects (including CSF cGMP) with E2027 
effects on various efficacy endpoints, if data permit

To explore collected pharmacogenomic (PGx) samples by investigating heterogeneity in clinical 
features of disease, including differences in baseline characteristics as well as response to 
compound (efficacy, safety and/or absorption, distribution, metabolism, and excretion 
[ADME]). These exploratory analyses are not limited to this protocol or project.  These findings 
may be used for identification and validation of new drug targets.
Study Design
This is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study in subjects
with DLB who will be treated with placebo or E2027 (50 mg once daily [QD]) for 12 weeks.  
In some of the countries selected for this study, donepezil is approved for DLB, with
acetylcholinesterase inhibitors (AChEIs) and increasingly memantine often used as part of standard 
care in patients with DLB.  Therefore, the study design allows for add-on therapy to standard of care 
for DLB, which includes AChEI and/or memantine at stable doses, except for any prohibited 
medications specified in this protocol.  Subjects who are not receiving AChEI or memantine are also 
eligible, but are not permitted to start such medications during the study.  (revised per 
Amendment 03)  Randomization will be stratified based on whether subjects are on a stabilized dose 
of AChEI or not and by geographical region (ie, North America, Europe, or Japan).  Up to 
approximately 20% of randomized subjects will be on memantine.  (revised per Amendment 04) 
Subjects will be randomly assigned to placebo or E2027 (50 mg QD) in a ratio of 1:1.
For all subjects, study participation will comprise 2 phases:  Prerandomization and Randomization.  
The Prerandomization Phase will last for up to 6 weeks and will include a Screening Period (up to 
5 weeks) and a Baseline Period (1 week).  The Randomization Phase will last for 16 weeks and will 
include a Treatment Period (12 weeks) and a Follow-up Period (4 weeks).  
Screening will occur between Day -42 and Day -8. The purpose of the Screening 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 subject and before the conduct of any screening procedures 
or assessments.  All subjects will be assessed for eligibility through review of medical history, 
physical examination (including neurological examination), laboratory tests, vital signs and 
electrocardiograms (ECGs).  They will be assessed on clinical scales of cognition and depression, 


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safety magnetic resonance imaging (MRI) of the brain and dopamine transporter (DAT) brain
imaging or myocardial scintigraphy ([123I]meta-iodobenzylguanidine [MIBG]) (if indicated in 
individual subjects and not previously performed) to confirm that they meet the diagnostic criteria
and severity for DLB.  Their motor features will be assessed on the Movement Disorders Society 
(MDS) Unified Parkinson’s Disease Rating Scale Part III:  Motor Examination (UPDRS-III) and 
staged by the Hoehn and Yahr Scale (HYS).  Their history of suicidality will be assessed by the 
Columbia Suicide Severity Rating Scale (C-SSRS).  They will also be assessed regarding other 
medical conditions and concomitant medications to ensure that these are stable with no changes to 
treatment required and that they do not interfere with their safety or study procedures.
Eligibility assessments at Screening will be conducted in tiers and subjects will need to satisfy 
eligibility criteria in each tier before proceeding to the next tier.  In Tier 1 demographics, medical 
history (including history of DLB and other medical conditions) and concomitant medications will 
be reviewed.  In Tier 2, clinical assessments on cognition and depression will be conducted in the 
morning (whenever possible) in subjects in the following order:  MMSE and Geriatric Depression 
Scale (GDS) should be done first, followed by the MoCA and SCOPA-Sleep.  The caregivers or 
informants will also complete the Short Fluctuation Questionnaire (SFQ), CFI, and the NPI.  If the 
eligibility criteria regarding the MMSE and GDS are not met, the other procedures (MoCA, SCOPA-
Sleep, SFQ, CFI, and NPI) do not have to be performed and the subject should be screen failed.  In 
Tier 3 subjects will be assessed with the Modified Hachinski Ischemic Scale, UPDRS-III, HYS, and 
C-SSRS.  In Tier 4 subjects will undertake physical examination, vital signs, ECG, and clinical 
laboratory tests.  In Tier 5, subjects will be assessed by safety MRI for brain abnormalities that may 
affect eligibility.  In Tier 6, if indicated as judged by the investigator, individual subjects may also 
undertake DAT brain imaging scan or myocardial MIBG scan to help establish their diagnosis.  It is 
recommended that where appropriate Tiers 1 to 4 should be performed on the same day and Tiers 5 
and 6 on a separate day.  However, the investigator may perform the various tiers on separate days 
as appropriate for each subject.  The scores of various clinical scales (including NPI, SFQ, and 
UPDRS-III) and cognitive tests (MMSE, MoCA) at Screening will be reviewed by a central process.  
Subjects who are diagnosed by the investigator with DLB but whose scores on clinical scales or 
cognitive tests are found not to be consistent with the diagnosis during central review will be 
discussed with the investigator to determine their eligibility.  
Due to the intrinsic variability of cognitive functions in DLB, subjects who screen fail at Tier 2 may 
be rescreened after at least 30 days, but as a guide, rescreening frequency should not be more frequent 
than once every 4 months and a subject should not be rescreened more than 2 times under the same 
version of the eligibility criteria.  Subjects who are deemed eligible after passing all tiers at Screening 
will proceed to the Baseline Visit.
The baseline visit may take place at any time up to 7 days before the first dose of study drug (Day 1, 
ie, during Day -7 to Day -1, but should take place at least 2 weeks after the Screening Visit Tier 2 
assessments).  In subjects who had DAT brain imaging scan or MIBG myocardial scan during 
Screening, the Baseline Visit should take place at least 1 week after the scan.  Study assessments 
should be conducted in the morning (whenever possible).  Cognition will be assessed by the MoCA, 
which must be the first clinical scale to be administered before any invasive procedures.  It is 
recommended that after the MoCA the following efficacy assessments in subjects should be 
performed in the following overall order (other study assessments may be conducted in between
these efficacy assessments):  CIBIS-Plus and SCOPA-Sleep.  The subject will be interviewed to 
complete the DEMQOL.  The EQ-5D will be self-administered and completed by the subject.  The 
caregiver or informant will also complete the CIBIS-Plus, NPI, CFI, EQ-5D Proxy and will be 
interviewed to complete the DEMQOL-Proxy.  The rater administering the CIBIS-Plus should be 
independent of the rater(s) who administer the other clinical scales.  


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At Baseline Visit subjects will be assessed regarding other medical conditions and concomitant 
medications (including medications for DLB) to ensure that these remain stable with no changes to 
treatment required and that they do not interfere with their safety or study procedures.  Other safety 
assessment including vital signs, ECGs, laboratory tests, and C-SSRS will also be conducted.  
After completing study assessments at the Baseline Visit, subjects who continue to be eligible will 
proceed to the Randomization Phase, and will be randomly assigned to placebo or E2027 (50 mg 
QD).  They will be provided with study drug (placebo or E2027) to start administration in the 
morning of Day 1 at home.  They will continue to take study drug for 12 weeks.  During the 
Treatment Period study visits will be conducted after 2, 4, 6, 9 and 12 weeks on study drug.  Safety 
assessments will be conducted at all these visits.  Efficacy assessments will be performed after 6 and 
12 weeks on study drug and should be performed at approximately the same time of the day as at the 
Baseline Visit whenever possible (preferably in the morning).  The MoCA should be the first clinical 
scale to be administered before any invasive procedures.  Whenever possible, a subject should have 
the same rater administering the MoCA and the CIBIC-Plus throughout his/her participation in the 
study.  It is recommended that other efficacy assessments in subjects should be performed in the 
following order (other study assessments may be conducted in between these efficacy assessments):  
CIBIC-Plus, MMSE (after 12 weeks only), and SCOPA-Sleep.  The rater administering the CIBIC-
Plus should be independent of the rater(s) who administer the other clinical scales.  The subject will 
self-complete the EQ-5D.  The caregiver or informant will also complete the CIBIC-Plus, NPI, CFI, 
and EQ-5D Proxy Version 1.  In addition, at the study visit after 12 weeks on study drug interviews 
with the subject and the caregiver or informant will be conducted to complete the DEMQOL (subject) 
and DEMQOL-Proxy (caregiver or informant).  Safety assessments will be conducted at these visits, 
including review of adverse events (AEs), vital signs, ECG, laboratory safety tests, C-SSRS, and 
UPDRS-III.  The investigator will review all the efficacy endpoints and safety data at the visits after 
6 weeks and 12 weeks on study drug and formulate the CGIC-DLB of the subject’s clinical status 
from Baseline.  
After the Treatment Period, subjects will complete a Follow-Up Visit 4 weeks after the final dose of 
study drug.  Efficacy assessments should be performed at approximately the same time of the day as 
at the Baseline Visit whenever possible (preferably in the morning).  The MoCA should be the first 
clinical scale to be administered before any invasive procedures.  It is recommended that other 
efficacy assessments in subjects should be performed in the following order (other study assessments 
may be conducted in between these efficacy assessments):  MMSE and SCOPA-Sleep.  The 
caregiver or informant will also complete the CFI and NPI.  Safety assessments will also be 
completed.  
The end of study is defined as the last subject completing the Follow-Up Visit.
Early Discontinuation
Subjects who prematurely discontinue study drug for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their final dose of study drug.  The safety and efficacy 
assessments normally performed after 12 weeks of treatment will be conducted at the ED Visit.  In 
addition, subjects who discontinue study drug are expected to continue in the study for the originally 
scheduled visits, starting with next such visit that is >7 days after the ED Visit.  Subjects who 
prematurely discontinue the study should attend at least 1 originally scheduled visit after the ED 
Visit. 


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CSF Substudy
A subset of subjects will participate in a substudy in which CSF will be collected by lumbar puncture 
(LP) during Screening and again during the Randomization Phase after 9 weeks of treatment on study 
drug.  Participation in the substudy will be voluntary.  After they have completed all screening 
assessments and are deemed eligible for the study, a baseline CSF sample will be collected at least 
7 days before the Baseline Visit.  If necessary, in these subjects the Screening Period may be 
extended by 1 week after discussion with the sponsor medical monitor. After they have completed 
9 weeks of treatment, they will have a 2nd CSF sample collected.  The CSF samples will be collected 
in the morning at approximately the same time, either in the fasted state (preferred) or at least 2 hours 
after breakfast.
As data permit, CSF cGMP will be assayed to evaluate the PD effects of E2027 in these subjects 
with DLB.  Other CSF PD biomarkers related to DLB or E2027 PD effects may also be assayed if 
appropriate.  CSF E2027 concentrations will also be determined.
Data Safety Monitoring Board
An independent data safety monitoring board (DSMB) will convene at regular intervals to monitor 
the overall safety of the study and to make recommendations to the sponsor related to study safety 
as appropriate.  The DSMB will be asked to review the cumulative safety data up to the date 
identified to make a determination if the study is safe to proceed unchanged or to provide 
recommendations to the sponsor as to how to proceed.  The study will proceed, including 
randomization of additional subjects, during DSMB safety reviews.  Details will be provided in the 
DSMB Charter.
Number of Subjects
Approximately 260 subjects will be screened to provide a maximum of 182 randomized subjects.  
Allowing for a 12% dropout rate, 160 randomized subjects are expected to complete the study.  
Participation in the CSF substudy is voluntary. It is estimated that approximately 30% of subjects 
will participate in the CSF substudy.
Inclusion Criteria
1.
Male or female, age 50 to 85 years, inclusive at time of consent.
2.
Meet criteria for probable DLB (as defined by the 4th report of the DLB Consortium) 
(Appendix 1). Specific situations regarding the use the imaging are described below:
a.
have 1 core clinical feature only by the investigator and who did not have previous reports 
of DAT brain imaging scan, MIBG scan or polysomnography (PSG) will undertake DAT
brain imaging scan or MIBG scan as organized by the investigator.  
b.
have 2 or more core clinical features by the investigator but who are judged as having only 
1 core clinical feature by central reviewer and who did not have previous reports of DAT
brain imaging scan, MIBG scan or PSG may undertake DAT brain imaging scan or MIBG 
scan after discussion with the sponsor medical monitor.
c.
have 2 or more core clinical features by the investigator and the central reviewer and who 
did not have previous reports of DAT brain imaging scan, MIBG scan or PSG may 
undertake DAT brain imaging scan or MIBG scan after discussion with the sponsor medical 
monitor if the investigator considers that imaging is necessary to confirm the diagnosis.
Where there are local/national regulatory requirements for additional central regulatory review 
of radiation exposure for the use of DAT / MIBG scans, enrollment of subjects is restricted to 


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those who do not require a new DAT / MIBG scan conducted under this study (ie, subjects who 
have historical DAT/MIBG scan/PSG results, or subjects who have 2 core clinical features of 
DLB) until such approval is granted by the regulatory authority on radiation exposure. Thereafter 
enrollment of subjects will extend to those who may require a new DAT / MIBG scan under this 
study.  (revised per Amendment 01)
3.
MMSE >14 and <26 at Screening Visit.
4.
Has experienced visual hallucinations during the past 4 weeks before Screening Visit.  
5.
If receiving AChEIs, must have been on a stable dose for at least 12 weeks before Screening 
Visit, with no plans for dose adjustment during the study.  Treatment-naïve subjects can be 
entered into the study but there should be no plans to initiate treatment with AChEIs from 
Screening to the end of the study.
6.
If receiving memantine, must have been on a stable dose for at least 12 weeks before Screening 
Visit, with no plans for dose adjustment during the study.  Treatment naïve subjects can be 
entered into the study but there should be no plans to initiate treatment with memantine from 
Screening to the end of the study.  (revised per Amendment 03)
7.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, not be suffering from cognitive impairment, be sufficiently familiar with the 
subject and spend sufficient time with the subject on a regular basis such that the caregiver or 
informant can reliably fulfill the study requirements and must provide separate written consent.  
The caregiver or informant should normally be residing with the subject.  If the caregiver or 
informant is not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or informant is 
not with the subject.  As a guide the caregiver or informant should have contact with the subject 
on at least 4 days a week and each day for a total of at least 5 hours.  If in doubt about whether 
a subject's care arrangements are suitable for inclusion, the investigator should discuss this with 
the medical monitor.  At all visits caregivers or informants need to attend the visit in person 
along with the subject.  If during the study, the designated caregiver or informant relinquishes 
his/her responsibilities as caregiver or informant, a replacement caregiver or informant who 
meets the criteria above and who has similar knowledge of the subject’s clinical status from 
Baseline throughout the Treatment Period must be found.  If no such replacement caregiver or 
informant is available, the subject must be discontinued from the study.
8.
Provide written informed consent.  If a subject lacks capacity to consent in the investigator's 
opinion, the subject's assent should be obtained, as required in accordance with local laws, 
regulations and customs, plus the written informed consent of a legal representative should be 
obtained (capacity to consent and definition of legal representative should be determined in 
accordance with applicable local laws and regulations).  In countries where local laws, 
regulations, and customs do not permit subjects who lack capacity to consent to participate in 
this study, they will not be enrolled (revised per Amendment 02)
Exclusion Criteria
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
those caused by the subject’s DLB, including any comorbidities detected by clinical assessment 
or MRI.
2.
History of transient ischemic attacks or stroke within 12 months of Screening.


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3.
Modified Hachinski Ischemic Scale >4.
4.
Parkinsonian (extrapyramidal) features with Hoehn & Yahr stage IV or higher.
5.
Any major psychiatric diagnosis, including schizophrenia, bipolar disorder and current major 
depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition
(DSM-V).  
6.
GDS score >8.
7.
Severe visual or hearing impairment that may interfere with the subject study assessments 
including cognitive testing.
8.
History of deep brain stimulation or other neurosurgical procedure for Parkinson’s disease.
9.
Have thyroid stimulating hormone (TSH) above normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects whether or not they are 
taking thyroid supplements.
10. Abnormally low serum Vitamin B12 levels (less than the lower limit of normal [LLN]) for the 
testing laboratory (if subject is taking Vitamin B12 injections, level should be at or above the 
LLN for the testing laboratory).
11. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic 
metal implants (eg, in skull and cardiac devices other than those approved as safe for use in MRI 
scanners).  Subjects who require sedation for MRI or positron emission tomography (PET)
scanning as per local guidelines need not be excluded.
12. Evidence of other clinically significant lesions that suggest a dementia diagnosis other than DLB 
on brain MRI at Screening.  All MRIs will be acquired using a standardized procedure that will 
be outlined in the Imaging Charter and Imaging Acquisition Guidelines (IAG) and will be read 
by an approved centralized reader.
13. Other significant pathological findings on brain MRI at Screening, including but not limited to:  
any macrohemorrhage (greater than 10 mm at greatest diameter); an area of superficial siderosis; 
evidence of cerebral contusion, encephalomalacia, aneurysms, arteriovenous malformations, or 
infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular 
territory, severe small vessel or white matter disease; space occupying lesions; or brain tumors 
[however, lesions diagnosed as meningiomas or arachnoid cysts and less than or equal to 1 cm 
at their greatest diameter need not be exclusionary])
14. Hypersensitivity to E2027 or any of the excipients.  
15. A prolonged corrected QT interval calculated using Fridericia’s formula (QTcF) as demonstrated 
by triplicate ECG at the Screening or Baseline Visit (ie, mean value >450 msec).  
16. Had symptomatic orthostatic hypotension or symptomatic orthostatic tachycardia which resulted 
in hospitalization or urgent medical review in hospital in the past 12 months before Screening.
17. Any other clinically significant abnormalities that in the opinion of the investigator, require 
further investigation or treatment or that may interfere with study procedures or safety in the 
following:  

Physical examination, ECG, vital signs at Screening or Baseline Visit

Laboratory tests at Screening Visit


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18. Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma 
of the skin, or localized prostate cancer in male subjects).  Subjects who had malignant 
neoplasms but who have had at least 3 years of documented uninterrupted remission before 
Screening need not be excluded.  
19. Has a “yes” answer to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment 
within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized 
or treated for suicidal behavior in the past 5 years before Screening.  
20. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
21. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) which are 
not stably and adequately controlled, or which in the opinion of the investigator may affect the 
subject’s safety or interfere with the study assessments.
22. Taking any of the prohibited medications or not meeting the requirements regarding stable doses 
of permitted medications.
23. Participation in a clinical study involving any investigational drug/device for DLB within 
6 months before Screening or any other investigational drug/device in the 8 weeks or 5 half-lives 
(whichever is longer) of the study medication before Screening unless it can be documented that 
the subject was in a placebo treatment arm.
24. Planned surgery which requires general, spinal or epidural anesthesia that will take place during 
the study.  Planned surgery that requires only local anesthesia and can be undertaken as a day 
case without inpatient stay postoperatively need not result in exclusion if in the opinion of the 
investigator this operation does not interfere with study procedures and subject safety.
25. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin [hCG] 
test) with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG).  A separate 
baseline assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the first dose of study drug.
26. Females of childbearing potential.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing]).
27. For subjects who participate in the CSF substudy, the following exclusions apply:  

A bleeding disorder that is not under adequate control (including a plate count <50,000, 
international normalized ratio [INR] >1.5 or partial thromboplastin time [PTT] > upper 
limit of normal [ULN]).

Any contraindications to LP (eg, lower spinal malformation on physical examination, local 
spinal infection or other abnormality, or obesity to the extent that it makes LP technically 
difficult).


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Study Treatment(s)
Study drug should be administered QD orally in the morning with or without food.  Subjects will be 
instructed to take their other concomitant medications at the usual time.
Test drug:  E2027
E2027 will be administered in size #2 hypromellose (HPMC) capsules containing 25 mg of E2027.  
Subjects randomly assigned to E2027 dose will take 2 × E2027 25 mg capsules.  
Comparator Drug:  E2027-matched placebo capsules
Subjects randomly assigned to placebo will take 2 × E2027-matched placebo capsules QD.  
Duration of Treatment
All subjects will receive 12 weeks of treatment.
Concomitant Drug/Therapy
Prohibited and Restricted Concomitant Medications:  
Unless otherwise specified, the following medications are prohibited from a period of 14 days (or 
5 half-lives, whichever is longer) before the Baseline Visit (Visit 2) until the Follow-Up Visit to 
avoid the risk of interaction with E2027.  Subjects who start any of these medications during the 
study will be discontinued.

Drugs known to be strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A), which increase 
exposure of drugs that are CYP3A substrates by >5 fold, grapefruit, grapefruit juice, and 
grapefruit products.  

Drugs known to be moderate to strong inducers of CYP3A.  Herbal preparations containing St.  
John’s Wort is prohibited for 4 weeks before the Baseline Visit (Visit 2) until the Follow-Up 
Visit.  

Drugs known to cause prolongation of the QT interval, including but not limited to drugs that 
may cause cardiac arrhythmias.  For drugs which may cause QTcF prolongation, subjects need 
not be excluded if at Screening the subjects are already on stable doses for at least 4 weeks and 
their mean QTcF on triplicate ECGs at Screening and Baseline Visit is not >450 ms (Exclusion 
Criterion 15).  

Drugs that are phosphodiesterase inhibitors (eg, theophylline, aminophylline, sildenafil, 
tadalafil, vardenafil, dipyridamole, roflumilast, apremilast, inamrinone, milrinone, and 
enoximone)
The following medications are prohibited to avoid the risk of interference with study assessments or 
procedures.  Subjects who start these medications during the study will be discontinued unless 
otherwise specified.

Anticholinergic drugs that have central nervous system (CNS) activity are prohibited from 
4 weeks before Screening Visit until the Follow-Up Visit.

Pimavanserin is prohibited for 12 weeks before Screening Visit until the Follow-Up Visit.  
(revised per Amendment 03)

In subjects who participate in the CSF substudy only, anticoagulants (eg, heparin, heparin 
derivatives, non-heparin derivatives, warfarin, dabigatran) and dual antiplatelet therapy (eg, 
aspirin and clopidogrel together) are prohibited from Screening Visit until after the 2nd CSF 
collection at 9 weeks postrandomization.  These subjects who start anticoagulants or dual 
antiplatelet therapy at any time before CSF collection at 9 weeks postrandomization will not 
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The following restrictions apply to AChEIs (including donepezil, rivastigmine, galantamine) for 
treatment of DLB:

If a subject is already receiving AChEI at Screening, they must be on a stable dose for at least 
12 weeks before Screening and remain on the same dose during the study until the Follow-Up 
Visit.

If a subject is not already receiving AChEI at Screening, then these should not have been used 
at least 12 weeks before Screening and AChEI should not be started during the study until the 
Follow-Up Visit.

As far as it is feasible subjects who start AChEI or change their dose of AChEI during the study 
should undertake an Unscheduled Visit before making such changes in their AChEI medications 
to undertake efficacy assessments (MoCA, CIBIC-Plus, MMSE, SCOPA-Sleep, NPI, CFI, 
CGIC-DLB) (unless they have been conducted within past 4 weeks).  This change in AChEI
medication is considered a protocol deviation; the handling of efficacy data collected after the 
change of these medications in the efficacy analyses is described under Statistical Methods.
The following restrictions apply to memantine for treatment of DLB (revised per Amendment 03):

If a subject is already receiving memantine at Screening, they must be on a stable dose for at 
least 12 weeks before Screening and remain on the same dose during the study until the 
Follow-Up Visit.

If a subject is not already receiving memantine at Screening, then this should not have been 
used at least 12 weeks before Screening and memantine should not be started during the study 
until the Follow-Up Visit.

As far as it is feasible subjects who start memantine or change their dose of memantine during 
the study should undertake an Unscheduled Visit before making such changes in their 
memantine to undertake efficacy assessments (MoCA, CIBIC-Plus, MMSE, SCOPA-Sleep, 
NPI, CFI, CGIC-DLB) (unless they have been conducted within past 4 weeks).  This change in 
memantine is considered a protocol deviation; the handling of efficacy data collected after the 
change of these medications in the efficacy analyses is described under Statistical Methods.
The following restrictions apply to medications for Parkinson’s disease or motor symptoms of DLB
(except CNS-active anticholinergic drugs that are prohibited as above):

If a subject is already on any of these medications at Screening, then they must be on a stable 
dose for at least 4 weeks before Screening and remain on the same dose during the study until 
the Follow-Up Visit.

If a subject is not already on any of these medications at Screening, then these should not be 
started during the study until the Follow-Up Visit.

Starting or changing the dose of these medications during the study is considered as a protocol 
deviation; the handling of efficacy data collected after the change of these medications in the 
efficacy analyses is described under Statistical Methods.  
The following restrictions apply to medications for antipsychotic or neuroleptic drugs, Yi Gan San, 
hypnotics, anxiolytics or antidepressants:

If a subject is already on any of these medications at Screening, then they must be on a stable 
dose for at least 4 weeks before Screening and remain on the same dose during the study until 
the Follow-Up Visit.

If a subject is not already on any of these medications at Screening, then these should not be 
started during the study until the Follow-Up Visit.

As far as it is feasible subjects who start or change their dose of these medications should 
undertake an Unscheduled Visit before making such changes in these medications to undertake 


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efficacy assessments (MoCA, CIBIC-Plus, MMSE, SCOPA-Sleep, NPI, CFI, CGIC-DLB) 
(unless they have been conducted within past 4 weeks).  This change in such medications is a 
protocol deviation and the handling of efficacy data collected after the change of these 
medications in the efficacy analyses is described under Statistical Methods.  
The following restrictions apply to other medications that the subject is taking at Screening or are 
started during the study:

These medications may be permitted if they are not included in the prohibited or restricted 
medications list above, and are considered by the investigator and sponsor medical monitor not 
to compromise study assessments or subject safety.

Permitted prior medications should be at a stable dose for at least 4 weeks before Screening and 
as far as possible remain on the same dose throughout the study.  

Subjects who change the dose of their permitted prior medications or who start permitted new 
medications during the study may continue in the study if the investigator and sponsor medical 
monitor consider that this will not compromise study assessments or subject safety.  

As needed (PRN) medications required for performing LP for CSF sampling are permitted in the 
CSF substudy.
Assessments
Efficacy Assessments
MoCA
This scale assesses different cognitive domains:  attention and concentration, executive functions, 
memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation.  It 
is reported to be useful to characterize global cognitive impairment in DLB.  The total possible score 
is 30 points; a score of 26 or above is considered normal.  
CIBIC-Plus
The CIBIC-Plus scale is designed to measure various domains that describe subject function:  
general, mental/cognitive state, behavior, and activities of daily living.  It is a semi-structured global 
rating derived from a comprehensive interview with the subject and caregiver or informant by an 
independent rater who has no access to the source data or other psychometric test scores conducted
postrandomization as part of the given protocol.
At Baseline Visit, the independent rater will use a related tool, the CIBIS-Plus.  This scale, which 
assesses disease severity on a 7-point scale from 1 = normal to 7 = extremely ill, establishes a point 
of reference for subsequent interviews using the CIBIC-Plus.  During study visits after 6 weeks and 
12 weeks on study drug, the rater will administer the CIBIC-Plus separately to the subject and the 
caregiver or informant.  At the end of each pair of interviews during each of these study visits, the 
rater alone will determine separately for each of the 4 domains whether the disease has improved, 
worsened, or remained unchanged since the evaluation at Baseline.  The CIBIC-Plus scores are:  
1 (marked improvement), 2 (moderate improvement), 3 (minimal improvement), 4 (no change), 
5 (minimal worsening), 6 (moderate worsening) and 7 (marked worsening).
NPI
This scale assesses frequency and severity of 12 neuropsychiatric symptoms commonly described in 
dementia patients:  delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime 
behaviors and appetite/eating changes.  The scale also assesses the degree of caregiver or informant 
distress engendered by each of the symptoms.  It is rated from 0 to 144 with high scores meaning a 


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greater neuropsychiatric disturbance.  A subscore covering the domains of delusions, hallucinations, 
apathy, and depression (NPI-4) will also be derived.  
MMSE
A 30-point scale that measures orientation to time and place, registration, immediate and delayed 
recall, attention, language, and drawing.  Scores range from 0 (most impaired) to 30 (no impairment).
CFI
This scale assesses cognitive fluctuation with the same format as the NPI.  It evaluates fluctuation in 
various domains including attention, ability to performance daily functions, orientation, verbal 
communication and behaviour.  It is scored based on frequency and severity with a score range of 
0 to 12.  The scale also assesses the degree of caregiver or informant distress engendered by the 
symptoms.
SCOPA-Sleep
There are sections for night time and daytime sleep.  There are 5 questions for night time sleep:  
(1) trouble falling asleep, (2) awakening during the night, (3) episodes lying awake too long at night, 
(4) early morning waking, and (5) patient’s impression whether they had adequate duration of sleep 
at night.  There are 6 questions for daytime sleep, (1) falling asleep unexpectedly during the day or 
evening, (2) falling asleep while sitting peacefully, (3) while watching television or reading, (4) while 
talking to someone, (5) trouble staying awake during the day or evening, and (6) experiencing falling 
asleep as a problem.
CGIC-DLB
The CGIC-DLB provides an overall clinician-determined summary measure of change from the 
subject’s clinical status at Baseline Visit that takes into account all available information from the 
efficacy endpoints above (which include cognitive function, non-cognitive symptoms, behaviour and 
the impact of the symptoms on the patient’s ability to function) and safety data.  
PK Assessments
Blood samples will be collected for the determination of plasma E2027 concentrations for PK 
analysis.  Two blood samples for PK will be drawn at Week 2:  at predose (within 30 minutes before 
dosing) and 1 to 3 hours postdose.  Three blood samples for PK will be drawn at Weeks 6 and 12:  
at predose (within 30 minutes before dosing), 1 to 3 hours, and 4 to 8 hours postdose.  Additionally, 
2 blood samples for PK will be drawn at Week 9:  1 at predose (30 minutes before dosing), and 
another at 1 to 4 hours postdose.  At these visits, subjects or their caregivers or informants will be 
instructed not to take their study drug at home on the day the blood samples for PK are collected.  
Instead, subjects will take their study drug at the clinic after the predose blood draw; then a postdose 
blood draw will be performed.  In addition, subjects or their caregivers or informant will be instructed
to record the time of study drug administration for the 2 days before these visits when self-
administered at home and this information will be collected and recorded on the electronic case report 
forms (eCRFs).  
In subjects who participate in the CSF substudy, CSF specimens will be collected for the 
determination of CSF E2027 concentrations at Week 9. At this visit, a predose blood sample for PK 
will be taken first, followed by CSF sampling. Study drug will then be administered to the subjects.  
PD Assessments
In subjects who participate in the CSF substudy, a CSF sample will be collected during the Screening 
Period (at least 7 days before the Baseline Visit) and after 9 weeks on study drug.  Both samples 
should be collected at approximately the same time in the morning, either in the fasted state 
(preferred) or at least 2 hours after breakfast.  The CSF sample during the Treatment Period should 


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be collected after the predose blood draw for PK analysis at the study visit after 9 weeks on study 
drug.  The CSF samples will be assayed for cGMP and E2027.  Other CSF PD biomarkers related to 
DLB or E2027 PD effects may also be assayed if appropriate.  
PGx Assessments
Blood samples will be collected as specified in the Schedule of Procedures/Assessments where 
feasible and in accordance with local regulations.  Participation in PGx assessments is voluntary and 
subjects must provide a separate informed consent before blood collection for PGx assessments. 
The PGx blood samples may be used to genotype common and rare genetic variants.  Data obtained 
from the PGx analysis will be used for research, to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of the 
subject.  The deoxyribonucleic acid (DNA) will not be used to determine or predict risks for diseases 
that an individual subject does not currently have.  Any sample may be stored for up to 15 years, 
based on country specific regulations to assist in any scientific research questions related to E2027
or DLB.  
Safety Assessments
Safety will be assessed by monitoring and recording all AEs, monitoring of hematology, blood 
chemistry and urinalysis, measurement of vital signs (including orthostatic changes), ECGs, and the 
performance of physical examinations, C-SSRS and UPDRS-III.  A safety brain MRI may also be 
performed at Unscheduled Visits if deemed appropriate by the investigator.
C-SSRS
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline Visits, 
every visit during the Treatment Period and at the Follow-Up Visit.
MDS UPDRS-III:  Motor Examination
This scale evaluates extrapyramidal features in motor function in Parkinson’s disease.  It contains 33 
items in 18 categories:  (1) speech, (2) facial expression, (3) rigidity, (4) finger tapping, (5) hand 
movements, (6) supinational and pronation movements of hands, (7) toe tapping, (8) leg agility, (9) 
arising from chair, (10) gait, (11) freezing of gait, (12) postural stability, (13) posture, (14) body 
bradykinesia, (15) postural tremor of hands, (16) kinetic tremor of hands, (17) rest tremor  amplitude 
and (18) constancy of rest tremor.  Each item is scored 0 to 4, giving a total score range 0 to 132.  As 
far as is practical, the motor assessments should be made with the subject in the “on” state at each 
visit and at the same time relative to the subject’s last dose of Parkinson’s disease medication (such 
as L-dopa). (revised per Amendment 01)
Other Assessments
DEMQOL and DEMQOL-Proxy
The DEMQOL and DEMQOL-Proxy are appropriate for use in subjects with mild-moderate 
dementia (MMSE ≥10).  The DEMQOL is a 28-item scale and DEMQOL-Proxy is a 31-item scale.  
Both are interview administered.  Should the subject progress to severe dementia during the course 
of the study, only the DEMQOL-Proxy should be administered.  There are 5 domains:  daily 
activities, health and well-being, cognitive functioning, social relationships and self-concept.  All 
items are given a score from 1 to 4 and summed to produce domain scores.  A general quality of life 
item is unscored.
EQ-5D
The EQ-5D is a widely used general health state and health utility scale to assess the impact of any 
health intervention on the patient’s general quality of life.  The health utility values are utilized as 
weights to life expectancy estimates and ultimately are used in a metric known as an incremental 


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cost effectiveness ratio (ICERs).  ICERs are used by health authorities to make key decisions that 
ultimately impact the relative funding of health interventions across multiple therapeutic areas based 
on their relative cost-effectiveness.  Thus, the EQ-5D is not specifically developed for any particular 
disease to allow this cross-therapeutic comparison.  The scale consists of 5 specific questions 
(regarding mobility [walking], self-care [washing and dressing], usual activities, pain/discomfort, 
and anxiety/depression) and 1 overall health rating.  The EQ-5D is selected in this study due to its 
brevity and content.  The EQ-5D-5L (5 levels of responses to each of the 5 questions) will be utilized 
in this study as it allows for a more granular assessment of the impact of intervention.  The proxy 
EQ-5D version is available as EQ-5D-5L (5 levels of responses to each of the 5 questions) and will 
be utilized to assess the caregiver’s or informant’s perspective of the subject’s health.  The proxy 
EQ-5D-5L is available in 2 versions:  Proxy version 1 where the caregiver or informant (the proxy) 
is asked to rate the subject’s health-related quality of life in their (the proxy’s) opinion and Proxy 
version 2 where the caregiver or informant (the proxy) is asked to rate how he/she (the proxy) thinks 
the subject would rate his/her own health-related quality of life, if the subject were able to 
communicate it.  Only Proxy version 1 will be utilized in this particular study.
Bioanalytical Methods
Plasma and CSF E2027 concentrations and those of its metabolites (if appropriate) will be measured 
using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay 
methods.  CSF cGMP concentrations will be measured using a validated LC-MS/MS assay method. 
Statistical Methods
Study Endpoints
Primary Endpoints

Change from baseline in the MoCA total score at 12 weeks of treatment

CIBIC-Plus scale at 12 weeks of treatment
Secondary Endpoints
(Order revised per Amendment 05)

CGIC-DLB scale at 12 weeks of treatment

Change from baseline at 12 weeks of treatment in the following endpoints:  
o
CFI score
o
MMSE total score
o
NPI total score, subscores and caregiver or informant distress score

Safety and tolerability of E2027 as measured by (revised per Amendment 02):
o
Incidence of adverse events including severe AEs, serious AEs, AEs resulting in 
discontinuation
o
Incidence of orthostatic hypotension and orthostatic tachycardia
o
Incidence of markedly abnormal laboratory values and shifts from baseline of laboratory 
values
o
Incidence of abnormal ECG parameters and abnormal ECG findings
o
Incidence of suicidality based on C-SSRS
o
Changes from baseline in the total score of Unified Parkinson’s Disease Rating Scale 
Part III:  Motor Examination (UPDRS-III).
Exploratory Endpoints

Change from baseline at 12 weeks of treatment in the following endpoints:  


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o
SCOPA-Sleep total score and subscores

Change from baseline at 12 weeks of treatment in the following endpoints:
o
Each of the 5 domain scores of the DEMQOL and DEMQOL-Proxy
o
EQ-5D utility score and EQ-5D health status rating

Percentage change from baseline in CSF cGMP concentration after 9 weeks of treatment
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postrandomization safety assessment

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postrandomization coprimary efficacy measurement

The Per Protocol Analysis Set (PPS) is the subset of subjects in the FAS who sufficiently 
complied with the protocol. It may include subjects who complete certain prespecified minimal 
exposure to the treatment and have no major protocol violations such as wrong diagnosis, error 
in treatment assignment, use of prohibited medication and poor compliance. The precise reasons 
for excluding subjects from the PPS will be fully defined and documented before database lock.

The PK Analysis Set is the group of subjects with at least 1 quantifiable plasma E2027 
concentration with a documented dosing history

The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1 PD
parameter

The PK/PD Analysis Set is a group of subjects with at least 1 quantifiable plasma E2027 
concentration, except for placebo subjects, and at least 1 PD measurement with a documented 
dosing history.
Efficacy Analyses
The significance level for all efficacy endpoint analyses is 0.05 (2-sided), unless otherwise stated, 
with no adjustments for multiplicity. The efficacy analyses will be performed on the FAS except per 
protocol analysis will be performed on the PPS.
Definitions of Baseline
Baseline for the primary and secondary efficacy endpoints is defined as the last pretreatment 
assessment.  An additional baseline, based on the mean of all prerandomization values at the 
Screening and Baseline assessment, will be explored due to assess potential prerandomization 
variability.  
Analysis for the Primary Efficacy Endpoints
E2027 is planned for use as a symptomatic treatment in subjects with DLB.  The treatment effect of 
E2027 may be confounded by the use of rescue medications during the study. For the purposes of 
statistical analysis, rescue medications are defined as medications for treatment of symptoms of DLB 
that are prohibited or restricted (as specified in Concomitant Drug/Therapy section above) and they 
are not used in accordance with the rules in Concomitant Drug/Therapy section. This confounding 
may mask the true treatment effect of E2027 in treating subjects with DLB.  The treatment effect of 
interest will be the efficacy as measured by coprimary endpoints that would be observed at 12 weeks 
without initiation or dose change of any prohibited or restricted medications as mentioned above
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efficacy or any other events related to treatment or study outcome.  The target population is DLB 
subjects defined by inclusion/exclusion criteria.
There are 2 coprimary efficacy endpoints, change from baseline in the MoCA total score at 12 weeks 
and CIBIC-Plus scale at 12 weeks.  Overall, there are 2 null hypotheses (H0) to be tested in the 
primary analysis:  

H01:  There is no difference in the mean change from baseline in the MoCA total score at 
12 weeks between E2027 and placebo.

H02:  the proportional odds ratio based on CIBIC-Plus scale at 12 weeks between E2027 
and placebo is equal to 1.
The corresponding 2 alternative hypotheses are that there is a difference in the mean change from 
baseline in MoCA total score at 12 weeks in this coprimary endpoint between E2027 and placebo,
and the proportional odds ratio based on CIBIC-Plus scale at 12 weeks between E2027 and placebo 
is not equal to 1.  The study will be considered positive if statistically significant improvement (at 
level of 0.05 (2-sided) or 0.025 (1-sided)) is observed in both coprimary endpoints in E2027. 
The change from baseline of MoCA total score for E2027 compared to placebo will be analysed 
using the approach proposed by Mehrotra, et al. (2017) with slight modification based on reasons for 
missing data.  The following is a list of reasons for missing data and their missing mechanisms: 

Data not observed because of dropouts due to AEs, lack of efficacy or  any other intercurrent 
events related to treatment or study outcome will be considered as missing not at random
(MNAR)

The effect had rescue medication not been made available to subjects prior to week 12 is not 
observable for subjects who initiated prohibited or restricted rescue medication. For these 
subjects, the data collected after initiation of prohibited rescue medication are assumed to 
contain no treatment effect in the E2027 treatment group. Technically, response data
collected after initiation of prohibited rescue medication will be treated as MNAR such that 
response data as MNAR in the E2027 treatment group would be imputed by the mean 
response in the placebo treatment group as described by the imputation method below.

Data not observed because of dropouts due to intercurrent events definitely not related to 
treatment or outcome (eg, withdraw consent due to logistical problems) will be considered 
as missing at random (MAR). All events will be classified unambiguously in the statistical 
analysis plan. 
The mean of missing endpoint values in the E2027 treatment group considered as MAR will be 
imputed using the mean of missing endpoint values of completers in the E2027 treatment group and 
the mean of missing endpoint values in E2027 treatment group considered as MNAR will be imputed 
by the mean of the overall endpoint distribution under placebo based on the above missing reasons 
and the corresponding missing mechanisms. The mean of the overall endpoint distribution under 
placebo will be obtained using mixed effects model of repeated measures (MMRM) within placebo 
group assuming MAR. Test statistics and the p-value will be obtained as described by Mehrotra,
et al. (2017).
The sensitivity analysis for MoCA will be a tipping point analysis based on control-based mean 
imputation proposed by Mehrotra, et al. (2017) in the same article, which is an increasingly more 
conservative means such that the P-value is equal to the prespecified alpha (0.025 [1-sided]).  Drug 
benefit is interpreted as convincing if the tipping point is worse than the mean placebo dropouts.
Additional sensitivity analysis for different classification of missing mechanism (ie, all missing data 
in the E2027 treatment group will be considered as MNAR regardless of reason of dropouts), will be 
provided. 


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In order to generate inputs for proposed primary and sensitivity analyses, a MMRM will be used in 
separate MMRM analyses for each treatment group for all randomized subjects as well as completers 
assuming MAR for both treatment groups. The model will be adjusted for baseline MoCA, visit 
(Week 6 and Week 12), randomization stratification variable (receiving AChEI or not, geographical 
region [North America, Europe, Japan]), and baseline MoCA × visit as fixed effects. An unstructured 
covariance matrix will be used to model the covariance of within subject effect. The values of 
baseline MoCA will be adjusted using the overall baseline mean of all study subjects in computing 
least square (LS)-means.
The primary analysis of the CIBIC-Plus scale at 12 weeks will be based on control-based pattern 
imputation at subject level (Yuan, 2014). The CIBIC-Plus scale at 12 weeks will be imputed as an 
ordinal response variable. The same missing reasons and corresponding missing mechanism as in 
the analysis of change from baseline in MoCA total score will be used in this analysis. Only the 
missing ordinal responses in E2027 treatment group considered as MNAR will be imputed by ordinal 
responses observed in the placebo group using a pattern-mixture model approach under MNAR 
assumption. Other missing ordinal responses will be imputed assuming MAR. The CIBIC-Plus 
scale at 12 weeks (observed or imputed) will be analysed using the proportional odds model, a special 
case of generalized linear mixed models (GLMM), in multiply imputed data sets.  The results 
obtained from all multiply imputed data sets will be combined for overall inference using Rubin's 
rules. The GLMM model will include treatment, randomization stratification variables (receiving
AChEI or not, geographical region [North America, Europe, Japan]) as fixed effects.  The model 
will be fitted using GLMM with a multinomial distribution and a cumulative logit link function. The 
proportional odds ratio estimate between E2027 and placebo, the corresponding 95% CI and P-
values will be presented.  
The sensitivity analysis for the CIBIC-Plus scale will be a tipping point analysis based on multiple 
imputation at subject level using the pattern mixture model approach (Yuan, 2014), which is based 
on an increasingly more conservative shift parameter (based on cumulative logit function values for
the CIBIC-Plus scale) such that the P-value is equal to the prespecified alpha (0.05 [2-sided]). 
Additional sensitivity analysis for different classification of missing mechanism (ie, all missing data 
will be considered as MNAR regardless of reason of dropouts), will be provided.
If the proportional odds assumption is contradicted by the observed data in either the entire 
population or any stratum, the GLMM method will be replaced by the nonparametric van Elteren 
test in both primary analysis and sensitivity analysis. The CIBIC-Plus scale at 12 weeks will be 
analysed using van Elteren test adjusting 2 randomization stratification variables (on stabilized 
AChEI dose or not; geographical region [North America, Europe, Japan]). The H0corresponding to 
the van Elteren test is that there is no difference in the location of distribution of the CIBIC-Plus 
scale at 12 weeks between E2027 and placebo. The corresponding alternative hypothesis is that there 
is a difference in the location of distribution of the CIBIC-Plus scale at 12 weeks between E2027 and 
placebo.
The potential effect of baseline MMSE on the primary result will be evaluated as an additional 
covariate in the primary model as appropriate.  Subgroup (eg, region, age group, baseline AChEI
status, baseline MMSE group, and baseline memantine status) analyses will be performed as 
appropriate.  (revised per Amendment 03)
Analyses for the Secondary Efficacy Endpoints
The CGIC-DLB scale will be analysed as ordinal response data in a manner similar to the primary 
analysis of coprimary endpoint based on CIBIC-Plus. Other secondary endpoints are continuous 


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variables and will be analyzed in a manner similar to the primary analysis of coprimary endpoint 
based on MoCA.  
Analyses for the Exploratory Efficacy Endpoints
The sleep endpoint (SCOPA-Sleep total score and subscores) will be analyzed in a manner similar
to the primary analysis of the coprimary endpoint based on MoCA.  
If data permit, the relationship between E2027 PD effects on CSF cGMP (and other biomarkers) and
various efficacy endpoints will be explored using correlation analysis and linear models will be fitted 
to further characterize the relationship between the changes in efficacy endpoints and the changes in 
E2027 PD variables as appropriate.
PK, PD, and PGx Analyses
PK Analyses
The PK Analysis Set will be used for plasma E2027 concentration listings and for summaries of CSF 
E2027 concentrations by dose and day.  
A population PK approach will be used to characterize plasma E2027 PK.  For this approach, PK 
data from this study will be pooled with existing data from Phase 1 studies.  The effect of covariates 
on plasma E2027 PK, such as baseline characteristics/demographics, will be evaluated where 
feasible.  Derived plasma E2027 exposure parameters, such as steady state area under the 
concentration time curve (AUCss) or average steady state concentration (Css,av), will be calculated 
from the final PK model using the individual posterior estimates of the PK parameters and dosing 
history.  
PD Analyses
The PD Analysis Set will be used for the summaries and analyses of CSF PD biomarkers.  The 
percentage change from baseline in CSF cGMP and any other PD biomarkers after at least 9 weeks 
of treatment with study drug postrandomization will be analyzed and presented graphically. 
PD/PK Analyses
Data combining Phase 1 studies, permitting a population PK/PD approach, will be used to 
characterize the relationship between plasma and/or CSF E2027 exposures and CSF PD biomarker 
levels.  For this approach, data from this study will be pooled with relevant data from Phase 1 studies.  
The relationship between plasma and CSF E2027 exposure and the change from baseline of various 
efficacy endpoints will be explored graphically, as will the relationship between changes in CSF PD 
biomarkers and the change from baseline of various efficacy endpoints.  Any emergent relationships 
will be explored through population PK/PD modeling.
PGx Analyses
Pharmacogenomic analyses may be performed and reported separately.  Details of these analyses 
may be described in a separate analysis plan. 
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs, out-of-
normal-range laboratory safety test variables, abnormal ECG findings, and out-of-range vital signs, 
suicidality (C-SSRS), UPDRS-III, along with change from baseline in laboratory safety test 
variables, ECGs, and vital sign measurements (including orthostatic changes) will be summarized 
by treatment group.  


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Other Analyses
The quality of life endpoints (DEMQOL and DEMQOL-Proxy domain scores, and the EQ-5D and 
EQ-5D Proxy scores) after 12 weeks of treatment and the percentage change from baseline in CSF 
cGMP concentrations after 9 weeks of treatment will be analysed using ANCOVA or rank-based 
ANCOVA as appropriate.  The ANCOVA model will include baseline as a covariate, with treatment 
group and randomization stratification variables as factors.
Interim Analyses
This is a fixed design.  There is no interim analysis of efficacy and no alpha spending before final 
analysis.  (revised per Amendment 03)
Sample Size Rationale
The MoCA scale was assessed in DLB subjects and reported by Biundo et al. (2016).  The observed 
mean change from baseline in the MoCA total score at 1 year in this report is -1.04 points and the 
corresponding standard deviation (SD) is 1.32 points.  An estimation of the mean change from 
baseline in the MoCA total score at 3 months is approximately -0.26 points using linear interpolation.  
It is assumed that E2027 would improve the MoCA total score as compared with baseline and achieve 
a mean treatment difference of approximately 0.6 points between E2027 and placebo at 12 weeks.  
The SD of change from baseline in the MoCA total score at 3 months is expected to be smaller than 
that at 1 year.  A conservative estimate of the SD of change from baseline in the MoCA total score 
is 1.3 points at 12 weeks. 
In a 12-week donepezil monotherapy study in subjects with DLB (E2020-J081-431), the estimated 
proportional odds ratio based on the CIBIC-Plus scale for donepezil 10 mg relative to placebo was 
6.14.  It is assumed that E2027 would achieve a proportional odds ratio of 2.607 relative to placebo 
(ie, 42% of the effect size observed in the above donepezil study). 
With 80 subjects completing per arm (for 91 randomized subjects per arm, assuming a 12% dropout 
rate), this study will have approximately 80% power to detect the above effect sizes (ie, mean 
treatment difference of approximately 0.6 points based MoCA total score and proportional odds ratio 
of 2.607 based on CIBIC-Plus scale for E2027 relative to placebo) in both coprimary endpoints 
simultaneously.  Therefore, the total sample size of 182 randomized subjects is planned, assuming a 
12% dropout rate.
Participation in the CSF substudy is voluntary. It is estimated that approximately 30% of subjects 
will participate in the CSF substudy. If the dropout rate in the CSF substudy is 12%, 20%, or 50%, 
then the number of subjects having final CSF assessment would be approximately 48, 44, or 27, 
respectively. 
The estimated standard deviation of percent change from baseline of cGMP
concentrations after 9 weeks of treatment from pooled subjects in the CSF substudy is approximately 
130%. The width of the 95% CI of the mean difference of percent change from baseline of cGMP 
concentrations after 9 weeks of treatment between E2027 and placebo for the 3 different sample sizes 
above would be approximately 74%, 77%, or 96%, respectively. Since mean percent change from 
baseline of cGMP concentrations after 9 weeks of treatment in the E2027 and placebo groups are
expected to be approximately 200% and 5%, respectively, the sample size of the CSF substudy would 
be adequate to detect the mean difference of percent change from baseline of cGMP concentrations 
after 9 weeks of treatment between E2027 and placebo groups.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................21
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................26
5
ETHICS.......................................................................................................................30
5.1
Institutional Review Boards/Independent Ethics Committees.............................30
5.2
Ethical Conduct of the Study..............................................................................31
5.3
Subject Information and Informed Consent ........................................................31
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................32
7
INTRODUCTION.......................................................................................................33
7.1
Indication...........................................................................................................33
7.1.1
Current Therapeutic Options.....................................................................33
7.1.1.1
Therapeutic Pathway.........................................................................34
7.1.1.2
Clinical Experience With E2027.......................................................34
7.1.1.2.1
Pharmacokinetics and Pharmacodynamics ..................................34
7.1.1.2.2
Safety and Tolerability................................................................36
7.1.1.3
Nonclinical Experience (revised per Amendment 05)........................39
7.2
Study Rationale..................................................................................................42
7.2.1
Study Overview........................................................................................42
7.2.2
Risk-Benefit Summary (revised per Amendments 02 and 05)...................43
8
STUDY OBJECTIVES................................................................................................44
8.1
Primary Objectives.............................................................................................44
8.2
Secondary Objectives.........................................................................................45
8.3
Exploratory Objectives.......................................................................................45
9
INVESTIGATIONAL PLAN ......................................................................................45
9.1
Overall Study Design and Plan...........................................................................45
9.1.1
Screening Period ......................................................................................46
9.1.2
Baseline Period.........................................................................................48
9.1.3
Randomization Phase/Treatment Period ...................................................48
9.1.3.1
CSF Substudy...................................................................................49
9.1.4
Follow-Up Period.....................................................................................49
9.1.5
Data Safety Monitoring Board..................................................................50
9.2
Discussion of Study Design, Including Choice of Control Groups......................50
9.3
Selection of Study Population ............................................................................52
9.3.1
Inclusion Criteria......................................................................................52
9.3.2
Exclusion Criteria.....................................................................................54


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9.3.3
Removal of Subjects From Therapy or Assessment ..................................56
9.4
Treatment(s).......................................................................................................56
9.4.1
Treatments Administered..........................................................................56
9.4.2
Identity of Investigational Product(s)........................................................57
9.4.2.1
Chemical Name, Structural Formula of E2027..................................57
9.4.2.2
Comparator Drug..............................................................................57
9.4.2.3
Labeling for Study Drug ...................................................................57
9.4.2.4
Storage Conditions ...........................................................................57
9.4.3
Method of Assigning Subjects to Treatment Groups.................................58
9.4.4
Selection of Doses in the Study ................................................................58
9.4.5
Selection and Timing of Dose for Each Subject........................................58
9.4.6
Blinding ...................................................................................................59
9.4.7
Prior and Concomitant Therapy................................................................59
9.4.7.1
Drug-Drug Interactions.....................................................................59
9.4.7.2
Prohibited and Restricted Concomitant Therapies and Drugs ............59
9.4.7.3
Other Restrictions.............................................................................62
9.4.8
Treatment Compliance .............................................................................62
9.4.9
Drug Supplies and Accountability ............................................................63
9.5
Study Assessments.............................................................................................64
9.5.1
Assessments .............................................................................................64
9.5.1.1
Demography.....................................................................................64
9.5.1.2
Baseline/Screening Assessments.......................................................64
9.5.1.2.1
Medical History and Physical Examinations................................64
9.5.1.2.2
Other Screening/Baseline Assessments .......................................65
9.5.1.3
Efficacy Assessments .......................................................................66
9.5.1.3.1
Montreal Cognitive Assessment (MoCA)....................................67
9.5.1.3.2
Clinician’s Interview Based Impression of Change Plus 
Caregiver Input (CIBIC-Plus) .....................................................67
9.5.1.3.3
Neuropsychiatric Inventory (NPI) ...............................................67
9.5.1.3.4
Mini-Mental State Examination (MMSE)....................................68
9.5.1.3.5
Cognitive Fluctuation Inventory (CFI) ........................................68
9.5.1.3.6
Scales for Outcome in Parkinson’s disease-Sleep (SCOPA-
Sleep) .........................................................................................68
9.5.1.3.7
Clinician Global Impression of Change in Dementia with Lewy 
Bodies (CGIC-DLB)...................................................................68
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................68
9.5.1.4.1
Pharmacokinetic Assessments.....................................................68


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9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments................................................................................69
9.5.1.5
Safety Assessments...........................................................................70
9.5.1.5.1
Adverse Events...........................................................................70
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................73
9.5.1.5.3
Study-Specific Adverse Events ...................................................74
9.5.1.5.4
Laboratory Measurements...........................................................74
9.5.1.5.5
Vital Signs, Height and Weight Measurements............................75
9.5.1.5.6
Physical Examinations ................................................................76
9.5.1.5.7
Electrocardiograms .....................................................................76
9.5.1.5.8
Other Safety Assessments ...........................................................77
9.5.1.6
Other Assessments............................................................................77
9.5.1.6.1
Dementia-related quality of life as assessed by the Dementia 
Quality of Life Measure (DEMQOL; interview of subject) and 
Dementia Quality of Life Measure by Proxy (DEMQOL-
Proxy; interview of caregiver about subject) ...............................77
9.5.1.6.2
General health status as assessed by the EuroQol- 5 Dimension 
questionnaire (EQ-5D; completed by subject) and EuroQol- 5 
Dimensions questionnaire by Proxy Version 1 (EQ-5D Proxy; 
caregiver completion of report about subject)..............................77
9.5.2
Schedule of Procedures/Assessments........................................................78
9.5.2.1
Schedule of Procedures/Assessments................................................78
9.5.2.2
Description of Procedures/Assessments Schedule .............................84
9.5.3
Appropriateness of Measurements............................................................85
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................85
9.5.4.1
Reporting of Serious Adverse Events................................................85
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................86
9.5.4.3
Reporting of Events Associated with Special Situations....................86
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................86
9.5.4.3.2
Reporting of Study-Specific Events.............................................87
9.5.4.4
Expedited Reporting .........................................................................87
9.5.4.5
Breaking the Blind............................................................................87
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................87
9.5.5
Completion/Discontinuation of Subjects (revised per Amendments 02 
and 05) .....................................................................................................87
9.5.6
Abuse or Diversion of Study Drug............................................................89


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9.5.7
Confirmation of Medical Care by Another Physician................................90
9.6
Data Quality Assurance......................................................................................90
9.6.1
Data Collection.........................................................................................90
9.6.2
Clinical Data Management .......................................................................90
9.7
Statistical Methods.............................................................................................90
9.7.1
Statistical and Analytical Plans.................................................................91
9.7.1.1
Study Endpoints................................................................................91
9.7.1.1.1
Primary Endpoints ......................................................................91
9.7.1.1.2
Secondary Endpoints...................................................................91
9.7.1.1.3
Exploratory Endpoints ................................................................91
9.7.1.2
Definitions of Analysis Sets..............................................................92
9.7.1.3
Subject Disposition...........................................................................92
9.7.1.4
Demographic and Other Baseline Characteristics..............................93
9.7.1.5
Prior and Concomitant Therapy ........................................................93
9.7.1.6
Efficacy Analyses.............................................................................93
9.7.1.6.1
Primary Efficacy Analysis...........................................................93
9.7.1.6.2
Secondary Efficacy Analyses......................................................96
9.7.1.6.3
Exploratory Efficacy Analyses....................................................96
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................96
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................96
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .....................................................................................97
9.7.1.8
Safety Analyses ................................................................................97
9.7.1.8.1
Extent of Exposure......................................................................97
9.7.1.8.2
Adverse Events...........................................................................98
9.7.1.8.3
Laboratory Values.......................................................................98
9.7.1.8.4
Vital Signs ..................................................................................99
9.7.1.8.5
Electrocardiograms .....................................................................99
9.7.1.8.6
Other Safety Analyses.................................................................99
9.7.1.9
Other Analyses .................................................................................99
9.7.2
Determination of Sample Size ................................................................100
9.7.3
Interim Analysis.....................................................................................100
9.7.4
Other Statistical/Analytical Issues ..........................................................101
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................101
10
REFERENCE LIST...................................................................................................102
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....104
11.1
Changes to the Protocol....................................................................................104


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11.2
Adherence to the Protocol................................................................................104
11.3
Monitoring Procedures.....................................................................................104
11.4
Recording of Data............................................................................................105
11.5
Identification of Source Data............................................................................105
11.6
Retention of Records........................................................................................106
11.7
Auditing Procedures and Inspection .................................................................106
11.8
Handling of Study Drug ...................................................................................106
11.9
Publication of Results ......................................................................................107
11.10 Disclosure and Confidentiality .........................................................................107
11.11 Discontinuation of Study..................................................................................107
11.12 Subject Insurance and Indemnity......................................................................108
12
APPENDICES...........................................................................................................109
LIST OF IN-TEXT TABLES
Table 1
Mean PK Parameters and Mean Increase in CSF cGMP From Baseline 
at Steady State In Study E2027-A001-002..............................................36
Table 2
Incidence of Common Treatment Emergent Adverse Events (>5% 
Incidence Overall in Part A) in Subjects Administered E2027 or 
Placebo QD for 14 Days in Study E2027-A001-002 ...............................38
Table 3 
Incidence of Treatment-Emergent Orthostatic Hypotension and 
Orthostatic Tachycardia At Any Time During Treatment Period in 
Subjects Administered Doses of E2027 50 to 400 mg or Placebo QD 
for 14 Days in Study E2027-A001-002...................................................39
Table 4
Treatments Administered........................................................................57
Table 5
Clinical Laboratory Tests........................................................................75
Table 6
Schedule of Procedures/Assessments in Study E2027-G000-201............79
Table 7
Summary of Estimated Blood and CSF Sample Volumes .......................84
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2027-G000-201...............................................46
LIST OF APPENDICES
Appendix 1
Diagnostic Criteria for Probable Dementia With Lewy Bodies (DLB) ..110
Appendix 2
Sponsor’s Grading for Laboratory Values.............................................112
Appendix 3
Examples of Adverse Events That May Signal Drug Abuse Potential ...114
Appendix 4
Cerebrospinal Fluid (CSF) Substudy (revised per Amendment 02) .......117


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADME
absorption, distribution, metabolism, and excretion
ALT
alanine aminotransferase (serum glutamic pyruvic transaminase)
Amax
maximum change (%) of CSF cGMP concentration compared to baseline at 
a single time point within 30 hours postdose
Amin,ss
minimum change (%) of CSF cGMP concentration at steady state compared 
to baseline
ANCOVA
analysis of covariance
AST
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUAC
area under the CSF cGMP concentration- time curve
AUC
area under the concentration-time curve
AUC(0-24h)
area under the concentration-time curve from zero time to 24 hours postdose
AUC(0-96h)
area under the concentration-time curve from zero time to 96 hours postdose
AUC(0-144h)
area under the concentration-time curve from zero time to 144 hours 
postdose
AUCss
steady state area under the concentration time curve
AUC(0-inf)
area under the concentration-time curve from zero time extrapolated to 
infinite time
AUC(0-)
area under the concentration-time curve from zero time to time of last 
quantifiable concentration
BP
blood pressure
cAMP
cyclic adenosine monophosphate
Css,av
average steady state concentration
CI
confidence interval
CIBIC-Plus
Clinician’s Interview Based Impression of Change Plus Caregiver Input
CGIC-DLB
Clinician Global Impression of Change in Dementia with Lewy Bodies 
cGMP
cyclic guanosine monophosphate
CFI
Cognitive Fluctuation Inventory
CL/F
apparent total clearance following oral administration
Cmax
maximum observed concentration
Cmax,SS
maximum observed concentration at steady state
Cmin
minimum observed concentration
CNGCs
cyclic nucleotide-gated cation channels
CNS
central nervous system


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Abbreviation
Term
CRAs
Clinical research associates
eCRF
electronic case report form
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
CYP3A
cytochrome P450 3A
DAT
dopamine transporter
DBP
diastolic blood pressure
DEMQOL
Dementia Quality of Life Measure
DEMQOL-Proxy
Dementia Quality of Life Measure by Proxy
DLB
dementia with Lewy bodies
DNA
deoxyribonucleic acid
DSMB
data safety monitoring board
DSM-V
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition
ECG
Electrocardiogram(s)
ECL
enterochromaffin-like 
e-COA
Electronic Clinical Outcome Assessment
ED
early discontinuation
EQ-5D
EuroQol- 5 Dimension questionnaire
EQ-5D Proxy 
EuroQol- 5 Dimensions questionnaire by Proxy Version 1
ER
extended release
FAS
Full Analysis Set
GC
guanylyl cyclase
GDS
Geriatric Depression Scale
GGT
γ-glutamyl transpeptidase
GLMM
generalized linear mixed models
GM
geometric mean
GTP
guanosine triphosphate
H01, H02
null hypothesis 1 to 2, respectively
hCG
human chorionic gonadotropin
HPMC
hypromellose
HR
heart rate
HYS
Hoehn and Yahr Scale
IAG
Imaging Charter and Imaging Acquisition Guidelines
IC50
50% inhibitory concentration


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Abbreviation
Term
ICER
incremental cost effectiveness ratio
ICF
informed consent form
IEC
Independent Ethics Committee
INR
international normalized ratio
IUPAC
International Union of Pure and Applied Chemistry
IUS
intrauterine hormone-releasing system
IxRS
interactive voice and web response system
LBD
Lewy body dementias
LC-MS/MS
liquid chromatography with tandem mass spectrometry
LLN
lower limit of normal
LP
lumbar puncture
LS
least square
LTP
long-term potentiation
MAD
multiple-ascending dose study
MAR
missing at random
MDS
Movement Disorders Society
MIBG
123I-meta-iodobenzylguanidine
MMRM
mixed effects model of repeated measures
MMSE
Mini-Mental State Examination
MNAR
Missing not at random
MoCA
Montreal Cognitive Assessment
MRI
magnetic resonance imaging
NICE
National Institute for Health and Care Excellence
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
NPI
Neuropsychiatric Inventory
NPI-4
NPI subscore covering 4 domains:  delusions, hallucinations, apathy, and 
depression
N/A
not applicable
NOS
nitric oxide synthase
PD
Pharmacodynamic(s)
PDD
Parkinson disease dementia 
PDE
Phosphodiesterase(s)
PDE9A
phosphodiesterase 9
PET
positron emission tomography


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Abbreviation
Term
PGx
pharmacogenomic
PK
Pharmacokinetic(s)
PKG
cGMP-dependent protein kinase
POC
proof of concept
PPK
population pharmacokinetics
PPS
Per Protocol Analysis Set
PRN
as needed (pro re nata)
PSG
polysomnography
PTT
partial thromboplastin time
QD
once daily
QTcF
corrected QT interval calculated using Fridericia’s formula
RBC
red blood cell
REM
rapid eye movement
SAD
single ascending dose
SBP
systolic blood pressure
SCOPA-Sleep
Scales for Outcome in Parkinson’s disease-Sleep
SD
standard deviation
SFQ
Short Fluctuation Questionnaire
SOP
standard operating procedure
SPECT
single-photon emission computed tomography
t½
terminal elimination phase half-life
T3
triiodothyronine
T4
thyroxine
TEAEs
treatment-emergent adverse events
tmax
time to reach maximum peak concentration following drug administration
TFT
thyroid function tests
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPDRS-III
Unified Parkinson’s Disease Rating Scale Part III:  Motor Examination
WBC
white blood cell
β-hCG
beta-human chorionic gonadotropin
ΔAUAC(0-30h)
AUAC averaged over 30 hours postdose relative to baseline AUAC 
averaged over 3 hours predose for CSF cGMP, ie, 
(AUAC(0–30h)/30 - AUAC(-3–0h)/3)/(AUAC(-3–0h)/3)
ΔΔQTcF
placebo-corrected change-from-baseline in corrected QT interval calculated 
using Fridericia’s formula


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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 (eg, change in clinical research 
associate[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 (or if regionally required, the head of the medical institution) 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 (or if regionally required, the head of the medical institution) 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 (or if regionally required, the investigator and the relevant IRB via the 
head of the medical institution) 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.
Where appropriate, at the end of the study, the sponsor should notify the IRB/IEC and 
Competent Authority (CA) within 90 days.  The end of the study will be the date of the last 
study visit for the last subject in the study.  The sponsor should also provide the IRB/IEC with 
a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons for 
the termination/halt should be given.


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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 (2013)

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 Council for Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

A waiver from the IRB(s)/IEC(s) will be obtained before study initiation for non-US 
studies conducted under an Investigational New Drug application (IND).  

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be reported, 
as required, to the Competent Authorities of all involved EU member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No.  145, 
1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to each 
subject or caregiver (or informant) in accordance with applicable professional standards and 
local laws/regulations 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.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and explained 
to the subject or the subject’s legally acceptable representative, and after the subject or the 
subject’s legally acceptable representative has orally consented to the subject’s participation 


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in the study and, if capable of doing so, has signed and personally dated the ICF, the witness 
should sign and personally date the consent form.  The subject will be asked to sign an ICF 
before any study-specific procedures are performed.  No subject can enter the study before 
his/her informed consent has been obtained.
The subject’s capacity to consent must be assessed at periodic intervals during the course of 
the subject’s involvement in the study, including whenever any concern is expressed about the 
subject’s continued capacity to consent (eg, by the study partner or a subject’s family member).  
The method and frequency of the assessment of capacity to consent must be performed in 
accordance with applicable professional standards and local laws/regulations.  During the 
course of the study, should a subject, in the investigator's opinion, decline to the point of 
lacking capacity to consent, the investigator should obtain the assent of the subject and the 
consent of their designated representative per the applicable local laws/regulations and 
IRB/IEC standards in order for the subject to continue in the study.  In countries where local 
laws/regulations do not permit subjects lacking capacity to consent to participate in this study, 
then subjects who have declined to the point of lacking capacity to consent during the study 
will be discontinued. (revised per Amendment 02)
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study before any study-specific procedures are performed and will be 
provided with a written ICF for his or her participation in the study. The subject and caregiver 
or informant do not have to sign their ICF on the same day.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed and 
dated by the appropriate parties.  The original, signed ICF for each subject identified caregiver 
or informant will be verified by the sponsor and kept on file according to local procedures at 
the site.  
The subject or their designated representative per the applicable local laws/regulations and 
IRB/IEC standards 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.  
The communication of this information should be documented.
Subjects who agree to take part in the cerebrospinal fluid (CSF) substudy will be asked to 
provide separate written consent for these procedures. Subjects who agree to take part in 
pharmacogenomics (PGx) assessment will also be asked to provide separate written consent 
for this procedure.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 70 investigational sites in North America, Europe, and Japan.  
(revised per Amendment 03)


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The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO(s)) are listed in the 
investigator site files that are provided to each site.
7
INTRODUCTION
7.1
Indication
Lewy body dementias (LBD) are the second most common cause of dementia in subjects over 
65 years of age.  It comprises dementia with Lewy bodies (DLB) and Parkinson’s disease 
dementia (PDD), which are considered to be different ends of the same spectrum.  Both DLB 
and PDD share a common underlying pathology which involves deposition of cortical and 
subcortical Lewy bodies within neurons (comprising aggregates of alpha synuclein).  
Idiopathic Parkinson’s disease is a progressive neurodegenerative disorder characterized by 
tremor, rigidity, bradykinesia, and postural instability, with onset typically in middle to late 
life.  It is thought that up to 80% of patients with Parkinson’s disease develop dementia some 
years after the onset of the motor features and they are classified as having PDD.  In DLB, 
subjects develop dementia prior to or within 12 months (McKeith, et al., 2017) after the onset 
of the characteristic motor symptoms associated with Parkinson’s disease (Walker, et al., 
2015). 
LBD (in the form of both DLB and PDD) involve similar profiles of cognitive dysfunction 
affecting attention, executive function, visuospatial domains and memory (Aarsland, et al., 
2003, Walker, et al., 2015, Biundo, et al., 2016).  Often, more than 1 aspect of cognition is 
impaired, interfering with the patient’s daily, occupational or social functioning.  While 
generally progressive, LBD are characterized by fluctuations in cognition and levels of 
consciousness, visual hallucinations, delusions, depression, anxiety, or other behavioral 
disturbances.  Patients may also have autonomic impairment that may include urinary 
dysfunction and orthostatic hypotension, with susceptibility to falls early in the disease course.
Although both DLB and PDD are considered to be part of the same spectrum of LBD, there 
are some clinical differences.  DLB subjects develop dementia early in the course of their 
disease (McKeith, et al., 2017) compared to subjects with PDD.  Patients with PDD have motor 
symptoms for some years with a higher proportion taking medications for Parkinsonian motor 
symptoms (Noe, et al., 2004).  Neuropsychiatric features (such as visual hallucinations) and 
cognitive fluctuations are more prominent in DLB than in PDD.  In DLB ~30% of subjects 
have concurrent amyloid pathology in the brain similar to that in Alzheimer’s disease (AD), 
whereas brain amyloid levels are lower in PDD compared to DLB (Donaghy, et al., 2015).  
7.1.1
Current Therapeutic Options
There are no therapies currently available that alter the underlying neurodegenerative process 
of LBD.  A number of symptomatic therapies can improve patient quality of life, primarily 
through management of motor symptoms such as bradykinesia, rigidity and gait disturbance.  
Levodopa remains the most effective medication available for treating the motor features of 
Parkinson’s disease that occur in LBD.  Current therapy for cognitive deficits associated with 


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LBD is largely based on the use of acetylcholinesterase inhibitors (AChEIs), such as 
rivastigmine and donepezil.  Rivastigmine is approved in multiple countries for symptomatic 
treatment of cognitive deficits in PDD and donepezil is approved in several Asian countries 
including Japan and the Philippines for symptomatic treatment of DLB.  Memantine is also 
used in the treatment of DLB but its efficacy is small (Aarsland, et al., 2009).  (revised per 
Amendment 03)  With regard to neuropsychiatric symptoms, pimavanserin is approved for 
these symptoms in Parkinson’s disease.  AChEIs and antipsychotics such as risperidone, 
quetiapine, and olanzapine are also commonly used in clinical neurology practice for this 
purpose.  However, the efficacy of AChEI and antipsychotic drugs on cognitive symptoms and 
neuropsychiatric symptoms is modest.  In addition, there are concerns about worsening of 
parkinsonism by both AChEI and antipsychotics as well as special concerns about 
hypersensitivity to antipsychotics.  Therefore, there is need for further treatment benefit.
7.1.1.1
Therapeutic Pathway
E2027 is a novel highly selective and potent inhibitor of PDE9. PDE9 is primarily responsible 
for breakdown of cyclic guanosine monophosphate (cGMP) within the brain, and the decreased 
levels of this secondary messenger have been associated with lower cognitive function in 
subjects with AD.  By inhibiting PDE9, and therefore reducing breakdown of cGMP, E2027 
aims to restore cGMP levels within the brain, and therefore palliate the symptoms in LBD.
7.1.1.2
Clinical Experience With E2027
As of the cut-off date of 30 Oct 2017, E2027 has been evaluated in 2 completed studies (E2027-
A001-001 [Study 001] and E2027-A001-003 [Study 003]) and 1 ongoing study (E2027-A001-
002 [Study 002]).  Overall, 186 subjects have received single or multiple doses of E2027 or 
placebo in the completed and ongoing studies as of the cut-off date.  Of these, final or quality 
controlled data are available for 112 subjects administered single E2027 doses from 10 to 
1200 mg and for 36 subjects administered multiple doses of E2027 from 25 to 400 mg for 
2 weeks. 
Detailed description of clinical experience with E2027 is provided in the E2027 Global 
Investigator’s Brochure.  
7.1.1.2.1
PHARMACOKINETICS AND PHARMACODYNAMICS
In Study 001, healthy subjects (aged 18 to 50 years), E2027 was rapidly absorbed after single 
doses of 10 to 1200 mg, with most subjects having quantifiable plasma E2027 concentrations 
within 0.5 hour post-dose.  Across all doses, the median tmax ranged from 2 to 4 hours post-
dose and E2027 showed biphasic disposition after tmax.  During the initial phase, plasma E2027 
concentrations declined until approximately 12 hours post-dose and then remained relatively 
stable through 24 hours post-dose.  At all doses there were subjects who showed multiple 
secondary peaks during the first 24 hours post-dose.  It was possible that the secondary peaks 
were due to the absorption of E2027 occurring in multiple stages.  From 24 hours post-dose 
onwards, E2027 showed first order kinetics during the terminal elimination phase.  Mean 
half-life was ~30 hours across doses (10 to 1200 mg), with no trend of increasing half-life
values with increasing dose.  Overall the geometric mean (GM) Cmax and AUC(0-inf) values 


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increased sub-proportionally with increasing doses from 10 to 1200 mg.  Geometric mean 
CL/F values showed a trend to increase with increasing dose.  Over the E2027 dose range of 
10 to 1200 mg, less than 1% of unchanged E2027 was eliminated in urine, suggesting that renal 
excretion is not an important elimination pathway for E2027 in humans.
Administration of a single dose of E2027 100 mg after consuming a standardized high-fat and 
high-calorie meal resulted in a 44.4% increase in the GM Cmax and a 19.2% increase in the GM 
AUC(0-inf). 
This difference is not considered clinically significant and E2027 may be 
administered with or without food.
In healthy elderly subjects administered E2027 100 mg, the GM LS Cmax was approximately 
45.5% higher and GM LS AUC(0-inf) was approximately 41.5% higher than in younger healthy 
adult subjects.  The mean t½ in healthy elderly subjects was approximately 10 hours longer 
than in younger healthy adult subjects.
Preliminary PK data in Study 002, healthy subjects (aged 50 to 85) who were treated with 
E2027 at 25 mg to 400 mg QD for 14 days showed that after the first dose on Day 1, the PK 
profile was similar to that seen in the first time in human single ascending dose study.  
Thereafter, steady state was reached by Day 12.  After the final dose on Day 14, the steady 
state PK profile was similar to that of Day 1.  E2027 was rapidly absorbed with median tmax
ranging from 1.5 to 3.0 hours postdose.  Thereafter, plasma E2027 concentrations declined 
until approximately 12 hours postdose and then remained relatively stable to 24 hours postdose 
of Day 14.  At all doses there were subjects who showed secondary peaks at approximately 
24 hours postdose of Day 14.  From 24 hours postdose onwards, E2027 showed first order 
kinetics during the terminal elimination phase.  Mean half-life after Day 14 was similar across 
doses, at ~40 hours, with no trend of increasing half-life with increasing dose.  The 
accumulation ratios of Cmax and AUC(0-24h) were generally consistent with the estimate from 
single-dose PK (~2.95-fold accumulation). Overall the mean Cmax and AUC at steady state 
increased subproportionally with increasing doses from 25 to 400 mg, consistent with single 
dose PK characteristics.  For a 16-fold increase in dose from 25 to 400 mg, Cmax,ss increased 
by 8.4 fold and AUC(0-) increased by 7.7 fold. The ratio of CSF:plasma concentrations of 
E2027 at steady state was ~3.5%.
Healthy Japanese subjects administered E2027 400 mg QD for 14 days showed comparable 
Cmax,ss and AUC(0-) as non-Japanese subjects.  Their half-life and accumulation ratios at steady 
state were comparable to non-Japanese subjects administered E2027 400 mg QD. Therefore,
no dose adjustment compared to non-Japanese subjects is required when E2027 is administered 
to Japanese subjects. 
In the presence of diltiazem (as a strong CYP3A inhibitor and P-gp inhibitor) administered at 
steady state, the Cmax of a single dose of E2027 100 mg increased by 14% and AUC(0-inf)
increased by 51%.  Thus, diltiazem had a mild inhibitory interaction with E2027 metabolism. 
Therefore, it is anticipated that mild to moderate inhibitors of CYP3A and P-gp inhibitors will 
have minimal effects on E2027 PK and are not likely to be clinically significant. Therefore,
no dose adjustments are required when E2027 is administered with concomitant medications 
that are mild-to-moderate CYP3A inhibitors or P-gp inhibitors.


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In Study 002, subjects administered 5 to 400 mg QD for 14 days underwent CSF collection at 
baseline and at steady state on Day 13 near the end of their treatment to evaluate CSF PK and 
PD effects (CSF cGMP elevation).  In addition, there were subjects administered E2027 50 mg 
QD for 6 weeks who underwent CSF collection at baseline and at steady state on Day 13 and 
Day 41 to evaluate CSF PK and PD effects (CSF cGMP elevation). 
At all E2027 doses (5 mg QD to 400 mg QD for 14 days), there was an increase in CSF cGMP 
concentrations (PD effect) from baseline as shown in Table 1.  The distribution of the PD 
effects in CSF overlapped across various doses.  Although the mean PD effects in CSF were 
greater at E2027 100 mg QD × 14 days than 50 mg QD × 14 days, this could in part be due to 
a potential outlier in the 100 mg cohort.  In general, across all E2027 doses studied (25 –
400 mg QD × 14 days) there was no dose related increase in CSF cGMP concentrations.
Table 1
Mean PK Parameters and Mean Increase in CSF cGMP From 
Baseline at Steady State In Study E2027-A001-002
Dose
Cmax,ss
(ng/mL)
AUC(0-)
(ng·h/mL)
CSF cGMP↑ From Baseline Predose at 
Steady State
Amin,ss (%)
5 mg QD
61.7
865
34
10 mg QD
137
1940
94
25 mg QD
336
5210
170
50 mg QD
788
11800
191
100 mg QD
1020
16800
260
200 mg QD
1780
24300
201
400 mg QD
2395
43638
199
AUC(0-) = area under the concentration-time curve from zero time to time of last quantifiable 
concentration, Amin,ss = minimum change (%) of CSF cGMP concentration at steady state compared to 
baseline, cGMP = cyclic guanosine monophosphate, Cmax,ss = maximum observed concentration at steady 
state, CSF = cerebrospinal fluid, QD = once daily.
In subjects treated with 50 mg QD for 6 weeks it was found that the CSF cGMP increased from 
baseline by 229% on Day 13 and by 222% on Day 41. Thus the CSF PD effects were sustained 
over a treatment period of up to 6 weeks in subjects administered E2027 50 mg QD.
7.1.1.2.2
SAFETY AND TOLERABILITY
Single Dose Study 001
E2027 was well tolerated in healthy adult subjects when administered as single oral doses
across the dose range of 10 to 1200 mg. The maximum tolerated dose (MTD) was not reached 
within the 120-fold range of increasing doses.  There were no dose-related trends in the 
incidence of various treatment-emergent adverse events (TEAEs).  The most common TEAEs 
(reported in more than 1 subject) in Study 001 occurring in subjects treated with E2027 were 
headache (11.6%), postural orthostatic tachycardia (5.6%), dizziness (5.6%), insomnia (5.6%), 


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increased in orthostatic HR response (3.7%) and paresthesia (3.7%).  Headache appeared to 
have a higher incidence in subjects on placebo.  Most TEAEs were of mild severity.  
There were no clinically significant changes in hematology, biochemistry and urinalysis values 
or in BP, HR, respiratory rate, and body temperature associated with single doses of E2027 at 
10 mg to 1200 mg.  There were no dose-related trends to indicate that E2027 was associated 
with orthostatic tachycardia or orthostatic hypotension. There were no effects of E2027 on 
ECG morphology, HR, PR interval and QRS interval.  The exposure-response relationship of 
the QTcF showed that even at the Cmax at the highest doses of 800 to 1200 mg the upper 
90% CI of the QTcF was less than 10 ms in healthy subjects.
Multiple Dose Study 002
Doses of E2027 5 to 400 mg QD × 14 days were well-tolerated in healthy subjects (50 to 
85 years of age).  Based on the preliminary unblinded safety analysis at 25 to 400 mg QD, the 
most common TEAEs in non-Japanese subjects (with overall incidence >5%) treated with 
E2027 were post lumbar puncture syndrome (13.3%), back pain (10%), constipation (10%), 
headache (10%), dizziness (6.7%) and increased orthostatic HR response (6.7%) (Table 2).  
Other TEAEs affected only 1 subject across all 5 non-Japanese cohorts.  There were no dose-
related trends of higher incidence of TEAEs with increasing dose. 
In Japanese subjects on 400 mg QD the most common TEAE (affecting >1 subject in the 
cohort) was constipation.  One Japanese subject on E2027 400 mg QD developed a drug rash. 
The profile of TEAEs was similar between Japanese and non-Japanese subjects on the same 
dose of 400 mg QD.  There were no serious adverse events (SAEs), no severe AEs, and no 
AEs that required discontinuation of E2027. 


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Table 2
Incidence of Common Treatment Emergent Adverse Events (>5% 
Incidence Overall in Part A) in Subjects Administered E2027 or 
Placebo QD for 14 Days in Study E2027-A001-002
TEAE
Placebo
E2027
(N=10)
n (%)
Japanese
(N=2)
n (%)
25 mg 
(N=6)
n (%)
50 mg 
(N=6)
n (%)
100 mg 
(N=6)
n (%)
200 mg
(N=6)
n (%)
400 mg
(N=6)
n (%)
400 mg 
Japanese
(N=6)
n (%)
Totala
(N=30)
n (%)
Any TEAE
6 (60.0)
2 (100)
6 (100)
4 (66.7)
3 (50.0)
5 (83.3)
2 (33.3)
4 (66.7)
20 (66.7)
Post lumbar 
puncture 
syndrome
0
0
1 (16.7)
1 (16.7)
1 (16.7)
1 (16.7)
0
0
4 (13.3)
Back pain
1 (10.0)
0
1 (16.7)
0
2 (33.3)
0
0
0
3 (10.0)
Constipation
4 (40.0)
0
0
1 (16.7)
1 (16.7)
1 (16.7)
0
2 (33.3)
3 (10.0)
Headache
0
0
1 (16.7)
1 (16.7)
1 (16.7)
0
0
0
3 (10.0)
Dizziness
1 (10.0)
1 (50.0)
2 (33.3)
0
0
0
0
0
2 (6.7)
Orthostatic 
heart rate 
response 
increased
0
0
0
0
0
2 (33.3)
0
0
2 (6.7)
a:  Total does not include the E2027 400 mg cohort in Japanese Subjects.
At the time of protocol development, data for orthostatic hypotension by numerical criteria as 
defined in the protocol (SBP decrease by >20 mmHg or DBP decrease by >10 mmHg, with 
increase in HR by >20 beats/min) was available in placebo and across doses of E2027 50 to 
400 mg QD × 14 days. Treatment emergent (ie, not present at baseline) orthostatic hypotension 
by numerical criteria occurred in 2 (20%) subjects administered placebo and 8 (26.7%) 
subjects administered E2027 during the treatment period (Table 3), with similar overall 
incidence.  None of the subjects were symptomatic.  Specifically, at steady state from Day 7 
to 13, there was 1 subject in E2027 200 mg cohort (Day 10) and 2 subjects in the Japanese 
E2027 400 mg cohort (1 on Day 11 and 1 on Day 12) who had orthostatic hypotension postdose 
at ~tmax.  On Day 14 at 2 hours postdose there was 1 subject in the E2027 200 mg cohort with
orthostatic hypotension, but there were no subjects having orthostatic hypotension 
administered E2027 at other time points during Day 14.  Overall the incidence of orthostatic 
hypotension in subjects administered E2027 was low and occurred at sporadic time points.  
There were no dose-related trends in the incidence of orthostatic hypotension.  
Treatment emergent (ie, not present at baseline) orthostatic tachycardia by numerical criteria 
(HR increase by >30 beats/min with HR >100 beats/min) without orthostatic hypotension 
occurred in 3 (30%) subjects administered placebo and 7 (23.3%) subjects administered E2027 
during the treatment period, with similar overall incidence.  None of the subjects were 
symptomatic.  Specifically at E2027 steady state from Day 7 to 13, there were no subjects with 
orthostatic tachycardia whether on placebo or E2027 at the time of predose (ie, at Cmin) and at 
~tmax.  On Day 14 at 4 to 6 hours postdose, there were 1 to 2 subjects affected in the 100 and 


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400 mg cohorts (both non-Japanese and Japanese), but not at other doses.  At other time points 
on Day 14, there were no subjects administered E2027 with orthostatic tachycardia.  Overall,
the incidence of orthostatic tachycardia in subjects administered E2027 was low and occurred 
at sporadic time points.  There were no dose-related trends in the incidence of orthostatic 
tachycardia. 
There were 2 subjects in the E2027 200 mg cohort who had TEAEs of increased orthostatic 
HR response (standing HR increased by >20 beats/min compared to supine) without 
concomitant orthostatic hypotension, but they were not symptomatic.  There was 1 subject in 
the E2027 200 mg cohort and 1 subject in the Japanese E2027 400 mg cohort who had TEAEs
of orthostatic hypotension, but they were not symptoms.  In summary, it did not appear that 
E2027 caused orthostatic hypotension or orthostatic tachycardia. 
Table 3
Incidence of Treatment-Emergent Orthostatic Hypotension and 
Orthostatic Tachycardia At Any Time During Treatment Period in 
Subjects Administered Doses of E2027 50 to 400 mg or Placebo 
QD for 14 Days in Study E2027-A001-002
Placebo
E2027
(N=10)
n (%)
Japanese
(N=2)
n (%)
50 mg 
(N=6)
n (%)
100 mg 
(N=6)
n (%)
200 mg
(N=6)
n (%)
400 mg
(N=6)
n (%)
400 mg 
Japanese
(N=6)
n (%)
Total
(N=30)
n (%)
Orthostatic 
hypotension
2 (20.0)
0
0
2 (33.3)
2 (33.3)
1 (16.7)
3 (50.0)
8 (26.7)
Orthostatic 
tachycardia
3 (30.0)
0
1 (16.7)
3 (50.0)
0
2 (33.3)
1 (16.7)
7 (23.3)
Across the various doses, the mean HR and BP postdose were stable compared to predose.  
There were no clinically significant changes in ECG parameters and laboratory safety 
parameters.  The incidence of treatment-emergent laboratory safety parameters which were out 
of normal range across the various cohorts was low and there were no dose-related trends.  The 
mean values of laboratory safety parameters at all time points were similar among subjects 
treated with placebo and various doses of E2027.  It did not appear that E2027 caused changes 
to vital signs, ECG parameters or laboratory safety parameters compared to placebo. 
Preliminary analysis of the PK-QTcF relationship showed that at the plasma E2027 
concentrations of the 50 mg QD group, the upper 90% CI of the placebo-corrected change from 
baseline of the QTcF (ΔΔQTcF) was 3.41 ms (mean 0.71 ms).  It also showed that prolongation 
of the QTcF with upper 90% CI of >10 ms could be excluded at plasma E2027 concentrations 
up to 2500 ng/mL. This means that at a E2027 dose up to 200 mg QD, there is no prolongation 
of QTcF with upper 90% CI of >10 ms .
7.1.1.3
Nonclinical Experience (revised per Amendment 05)
To provide supporting evidence for this dose selection on Study 201 it is also proposed that a 
dose of 50 mg QD administered for 6 weeks in healthy subjects should be investigated to 


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confirm sustainability of its CSF PD effects.  Doses below 25 mg QD are being investigated 
to explore the dose-PD response relationship across a broader dose range to establish the 
minimum therapeutic dose for Study 201.
In the monkey cardiovascular (CV) study, the no observed adverse effect level (NOAEL) was 
100 mg/kg (Cmax=2250 ng/mL), and at doses of 300 mg/kg and 1000 mg/kg, E2027 caused an 
increase in heart rate, prolongation of QTc interval, and a decrease in core body temperature.  
At 300 mg/kg, heart rate was increased by 15.5% from control value at 1 hour postdose.  The 
QTc interval was prolonged by 5.5%
from control value at 2 hours postdose.  Body 
temperature was decreased by 0.20 °C from control value at 2 hours postdose.  At 1000 mg/kg, 
heart rate was increased by 28.7% from control value at 1 hour postdose.  The QTc interval 
was prolonged  by 15.0% from control value at 2 hours postdose.  Body temperature was 
decreased by 0.73°C from control value at 2 hours postdose.  In the monkey CV study by IV 
administration, at a dose of 5.4 mg/kg, there were no effects on HR, BP, ECG parameters, or 
body temperature.  At the end of the infusion, the plasma concentration of E2027 was 5770 
ng/mL.  The highest dose in Study 201 is proposed to be 50 mg QD.  The Cmax,ss of 50 mg QD 
is within the range of concentrations of E2027 which had no effects on HR, BP, ECG 
parameters, or body temperature in the monkey CV studies by oral or intravenous dosing.  
The toxicity of E2027 has been evaluated in oral repeated-dose toxicology studies of up to 
13 weeks duration in rats and cynomolgus monkeys.  
In the rat 2-week toxicology study, the NOAEL was 100 mg/kg; and at 1000 mg/kg, the key
findings were limited to regenerative changes in the stomach indicative of local irritation, and 
transient decrease in body temperature.  In the monkey 2-week toxicology study, the NOAEL 
was 30 mg/kg and E2027-related changes were limited to vomiting at 100 and 500 mg/kg, and 
histologic regenerative changes in the stomach indicative of local irritation at 500 mg/kg.  
For the rat 13-week toxicology study, due to polymorphism of CYP2D1, genotyped rats 
(low--clearance genotype) were used to ensure exposure following oral administration.  In the 
13-week genotyped rat study, several animals died or sacrificed moribund at 1000 mg/kg/day 
following up to 3 days and 10 days of treatment in females and males (toxicokinetics group 
only), respectively, preceded by central nervous system (CNS) related signs including 
decreased locomotor activity, hypothermia, lateral/prone position, ataxic gait, or bradypnea.  
The highest dose was reduced to 500 mg/kg in female rats from Day 4 onward; the highest 
dose of 1000 mg/kg/day was maintained in male rats without further event.  In the surviving 
animals, there were no remarkable clinical signs, although a few episodes of loose stool, 
decreased activity, and irregular respiration were found in a limited number of males.  Low 
body weight without significant changes in food consumption and slight decreases in red blood 
cell (RBC) parameters were also observed in males.  In histopathology, noteworthy test 
article-related changes were observed in the stomach in both sexes including 
hyperplasia/basophilia of neck cells and increased enterochromaffin-like (ECL) cells which 
was considered to be correlated with an increase in serum gastrin.


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In the lower dose groups (30 and 100 mg/kg/day) there were no test article-related changes 
with exception of salivation likely secondary to the palatability of dosing formulation in a 
limited number of animals at 100 mg/kg.
Nonclinical findings of note in the 13-week cynomolgus monkey study included vomiting that 
was observed at 100 mg/kg/day and above in several animals on multiple occasions.  A few 
episodes of drowsiness were also noted in 2 females treated at 500 mg/kg.  At 30 mg/kg, there 
were no test article-related changes.
In the 13-week toxicology studies, the NOAEL was 100 and 30 mg/kg in rats and monkeys, 
respectively.  
HP4, mono-hydroxylated E2027, is a potential disproportionate metabolite in humans.  Study 
E2027-A001-005 (Study 005: 
An Open-Label, Single-Dose Study to Determine the 
Metabolism and Elimination of [14C]E2027 in Healthy Male Subjects) has been recently 
completed.  Preliminary results of metabolite composition in plasma obtained from Study 005
indicated that parent E2027 was the major component with 62.5% of total plasma radioactivity 
(AUC(0-96h)), and HP4 was 6.3% of total plasma radioactivity (AUC(0-96h)). HP4 exposure was 
detected at only trace levels at the highest doses tested in rats and monkeys in chronic 
toxicology studies.
E2027 as well as HP4 were negative in Ames tests.  As exposure of HP4 was at trace levels 
only in previous studies in rats and monkeys, toxicological evaluation in mice was conducted
as a combination treatment of E2027 and HP4. 
E2027 was administered orally once a day for 4 weeks to male and female non-Tg rasH2 mice 
at a dose of 600 mg/kg alone or at a dose of 200, 400, or 600 mg/kg with HP4 given at a 
common dose of 20 mg/kg.  There were testicular changes in all treated groups, which was 
characterized by degeneration of the seminiferous epithelium associated with decreased 
testicular weight.  Spermatogonia appeared to be unaffected on histopathology, suggesting that 
the testicular changes are likely to be reversible.  There was no dose dependency in testicular 
findings among groups given the same dose of HP4 and different doses of E2027 (600/20, 
400/20, and 200/20 mg/kg groups, E2027/HP4 dose, respectively).  In mice dosed only with 
E2027 (600/0 mg/kg group), the incidence and severity of testicular changes were slightly 
lower than the other groups.
There were no testicular changes in the repeated-dose toxicity studies in rats (up to 26 weeks) 
or monkeys (up to 39 weeks).  
These results suggest that, although possible involvement of both E2027 and HP4 cannot be 
completely ruled out, HP4 is likely playing a greater role than E2027 in the induction of 
testicular toxicity.  Testicular toxicity was detected in non-Tg rasH2 mice at E2027 exposure 
multiple of 3.8-fold and at about 0.4 fold exposures of HP4 relative to the exposure of E2027 
and HP4, respectively, in humans treated with E2027 at 50 mg.  


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7.2
Study Rationale
Cyclic nucleotides such as cyclic adenosine monophosphate (cAMP) and cGMP work as 
second messengers in the intracellular signaling cascade, and play a critical role in learning 
and memory function in animal models (Domek-Łopacińska and Strosznajder, 2005).  Cyclic 
GMP is involved in the induction of hippocampal long-term potentiation (LTP) that is 
considered to be a neural substrate of cognitive function.  In the synaptic region, activation of 
N-methyl-D-aspartate (NMDA) receptors leads to nitric oxide synthase (NOS) activation via 
Ca2+ influx.  This is followed by activation of guanylyl cyclase (GC) by NO in both pre- and 
postsynaptic regions.  Subsequently, second messenger cGMP is synthesized from guanosine 
triphosphate (GTP) by GC.  cGMP activates cGMP-dependent protein kinase (PKG) and cyclic 
nucleotide-gated cation channels (CNGCs).  PKG phosphorylates various proteins and induces 
diverse physiological effects which are involved in synaptic plasticity.  Therefore, increase of 
cGMP in synaptic regions is expected to enhance LTP and consequently improve cognitive 
function.  Phosphodiesterases (PDE) hydrolyze cGMP by breaking the phosphodiester bond 
with guanosine monophosphate; thus, inhibition of PDE constitutes a mechanism whereby 
levels of cGMP can be increased.
In in vivo behavioral studies, inhibitors of NOS and GC are reported to impair cognitive
function, while GC activators, cGMP analogues, and PDE inhibitors enhance it.  Therefore,
compounds that enhance the NO-cGMP cascade are likely to improve cognitive function.  
PDE9 is a cGMP-degrading enzyme and expressed in brain, and its inhibitor is thought to 
increase neuronal cGMP and enhance cognitive function.  Therefore PDE9 inhibitors may be 
efficacious in neurodegenerative diseases with cognitive impairment such as LBD and AD.  
Subjects with AD have reduced CSF cGMP compared to healthy subjects and a PDE9 inhibitor 
which increases CNS cGMP may be specifically useful in AD and neurodegenerative diseases 
which have concomitant amyloid pathology similar to AD such as in DLB (Donaghy, et al.,
2015).  E2027 is a highly potent, selective, and orally available PDE9 inhibitor, which is being 
developed as a treatment for cognitive deficit in AD or LBD.  E2027 inhibits PDE9 with a 50% 
inhibitory concentration (IC50) of 3.5 nM and has more than 1000-fold selectivity over other 
enzymes of the PDE family.  Oral administration of E2027 significantly elevated CSF 
(sampled at ~tmax postdose) and hippocampal cGMP by 200% and 20%, respectively, in rat, 
and at the same dose improved object recognition memory.  It was also found that in animal 
cognition models E2027 improved cognition when administered alone or concurrently with 
donepezil. In the head twitch response animal model which represented a hyperserotoninergic 
behavior, E2027 reduced the number of head twitches, suggesting that it may also improve 
some of the neuropsychiatric symptoms in DLB (Study No. TP_DOI002_Mar2016).  Thus,
E2027 may improve cognition in DLB and AD via mechanistic pathways not directly involving 
cholinergic neurotransmission.  
7.2.1
Study Overview
The proposed study (E2027-G000-201; Study 201) is a Phase 2, randomized, double-blind, 
placebo-controlled study to determine the superiority of a dose of E2027 (50 mg QD) 
compared to placebo on various cognitive and neuropsychiatric endpoints in subjects with 
DLB.  Study 201 will also evaluate the safety, tolerability, PK, and PD effects of E2027.  


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Subjects with mild to moderate dementia due to DLB as diagnosed by established international 
guidelines are eligible.  In Study 201 subjects are eligible if they are not already established on 
AChEI and/or memantine (ie, naïve to standard treatment) or if they have been on a stable dose 
of an AChEI and/or memantine for at least 12 weeks before Screening.  (revised per 
Amendment 03)  Cognitive and neuropsychiatric assessments will be performed at Screening 
and Baseline.  Eligible subjects will be randomly assigned to placebo or a dose of E2027 (in a 
ratio of 1:1) for a Treatment Period of 12 weeks, during which efficacy and safety assessments 
will be conducted.  Randomization will be stratified by whether a subject is naïve to AChEI or 
established on a stable dose of AChEI and by geographical region (North America, EU, and 
Japan).  Up to approximately 20% of randomized subjects will be on memantine.  (revised per 
Amendment 04)  A follow-up visit will take place 4 weeks after the final dose of study drug.
The rationale for selection of one dose of E2027 (50 mg QD) is discussed in Section 9.4.4. 
The first primary efficacy endpoint (on cognition) will be the Montreal Cognitive Assessment 
(MoCA), which is a comprehensive cognitive endpoint evaluating various cognitive domains.  
The choice of the MoCA as primary endpoint is discussed in Section 9.2.  The coprimary 
efficacy endpoint on global clinical status will be the Clinician’s Interview Based Impression 
of Change Plus Caregiver Input (CIBIC-Plus).  The use of both coprimary endpoints (1 on 
cognition and 1 on global clinical status) is consistent with regulatory guidelines for clinical 
trials in dementia such that if E2027 shows positive results on both coprimary endpoints, the 
study may be considered as a pivotal study in future regulatory submissions.  For proof of 
concept (POC) purposes, the minimum requirement is that E2027 shows benefit on the 
cognitive endpoint (MoCA).
Secondary endpoints include the Neuropsychiatric Inventory (NPI), Mini-Mental State 
Examination (MMSE), Cognitive Fluctuation Inventory (CFI), and Clinical Global Impression 
of Change in Dementia with Lewy Bodies (CGIC-DLB).  Exploratory endpoints include Scales 
for Outcome in Parkinson’s disease—Sleep (SCOPA-Sleep) and percentage change from 
baseline of CSF cGMP (in subset of subjects who volunteer to undertake CSF sampling by 
lumbar puncture).  
7.2.2
Risk-Benefit Summary (revised per Amendments 02 and 05)
DLB is the proposed disease for this Phase 2 study given the limited range of current cognitive 
treatments in this disease. Given that current treatments (AChEI) for cognitive impairment in 
DLB typically achieve an improvement in MMSE by 1.5 to 3 points (McKeith, et al., 2000;
Mori, et al., 2012; Ikeda, et al., 2015), with MMSE on treatment with AChEI typically at 
23 points (Biundo, et al., 2016), there is room for further improvement of cognitive function 
in DLB compared to normal (MMSE >26).  
In subjects treated with 50 mg QD for 6 weeks it was found that the CSF cGMP increased from 
baseline by 229% on Day 13 and by 222% on Day 41.  Thus the CSF PD effects were sustained 
over a treatment period of up to 6 weeks in subjects administered E2027 50 mg QD. The E2027 
dose proposed in Study 201 of 50 mg QD is expected to achieve pharmacodynamics effects in 
CSF cGMP elevation from baseline by approximately 200% or more sustained throughout a 
dosing interval during chronic treatment with E2027. The proposed dose in Study 201 is 


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expected to achieve similar PD effects in CSF cGMP as in animal models with cognitive 
enhancement. Therefore, E2027 at 50 mg QD may show efficacy in cognition (increase in 
MoCA and MMSE scores) and possibly neuropsychiatric symptoms (reduction in NPI scores) 
in subjects with DLB. 
This dose of E2027 at 50 mg QD in Study 201 also has a safety margin of at least 2-fold relative 
to the exposure at the NOAEL dose in the 13-week toxicology studies in the most sensitive 
species.  The recent study in mice of the HP4 metabolite indicated that the HP4 metabolite is 
likely to be playing a role in testicular changes in mice. This occurred under the exposure of 
E2027 which was 3.8-fold the exposure in humans at 50 mg QD in the multiple ascending dose 
study (Study 002).  On the other hand, the testicular effects of HP4 occurred at mouse exposure 
which was 0.4-fold the concurrent human exposure (at E2027 50 mg in Study 005).  Although 
chronic treatment was not associated with testicular changes in rats and monkeys up to 26 or 
39 weeks, the human effect is yet to be evaluated.
Based on the Phase 1 clinical studies conducted to date, the proposed dose of E2027 at 50 mg 
QD is expected to be well-tolerated without causing clinically significant changes in vital 
signs, ECG parameters and laboratory safety parameters. Adverse events which were reported 
with E2027 include dizziness, headache, dry mouth, neck pain, postural orthostatic 
tachycardia, insomnia, skin rash, muscle stiffness, paresthesia, nausea, vomiting, lower 
abdominal pain, anxiety and restless legs. These adverse events were mild to moderate. 
Study 201 was initiated before the effects of HP4 metabolite in mice with testicular changes 
were known.  Given the CSF PD effects, well-tolerated clinical safety profile, and safety 
margin of the dose of E2027 in Study 201 relative to the NOAEL in the chronic rat and monkey 
toxicology studies, the sponsor considers that the risk-benefit balance is favorable for the 
investigation of E2027 in subjects with DLB at the proposed dose of 50 mg QD for 12 weeks.  
In view of the new findings of testicular changes in mice associated with the HP4 metabolite, 
the sponsor considers that because DLB is a progressive neurodegenerative condition with 
limited treatment options, the mean age of male subjects already randomized is 74 years old 
(range 55 to 85), and treatment duration of 12 weeks, male subjects already randomized in the 
study can continue under the risk management procedures proposed in Amendment 05 (see 
Section 9.4.7.3).
8
STUDY OBJECTIVES
8.1
Primary Objectives

To determine whether E2027 is superior to placebo on the cognitive endpoint of MoCA in 
subjects with DLB after 12 weeks of treatment

To determine whether E2027 is superior to placebo on the global clinical endpoint of 
CIBIC-Plus after 12 weeks of treatment


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8.2
Secondary Objectives
(Order of secondary objectives revised per Amendment 05)

To determine whether E2027 is superior to placebo on the following secondary endpoints 
after 12 weeks of treatment:
-
Clinician Global Impression of Change in Dementia with Lewy Bodies (CGIC-DLB)
-
Cognitive Fluctuation Inventory (CFI)
-
Mini-Mental State Examination (MMSE)
-
Neuropsychiatric Inventory (NPI)

To evaluate the safety and tolerability of E2027 in subjects with DLB

To characterize the population pharmacokinetics (PPK) of E2027 in subjects with DLB,
including evaluation of the effects of intrinsic and extrinsic factors on E2027 PK
8.3
Exploratory Objectives

To explore the efficacy of E2027 compared to placebo on the following endpoints after 
12 weeks of treatment:
-
Scales for Outcome in Parkinson’s disease-Sleep (SCOPA-Sleep)
-
Dementia-related quality of life as assessed by the Dementia Quality of Life Measure 
(DEMQOL; interview of subject) and Dementia Quality of Life Measure by Proxy 
(DEMQOL-Proxy; interview of caregiver or informant about subject)
-
General health status as assessed by the EuroQol- 5 Dimension questionnaire 
(EQ-5D; completed by subject) and EuroQol- 5 Dimensions questionnaire by Proxy 
Version 1 (EQ-5D Proxy; caregiver or informant completion of report about subject)

To evaluate the relationship between PK exposure of E2027 and its effects on various 
efficacy and safety endpoints

To explore the PK/PD relationship between the exposure of E2027 in CSF/plasma and its 
effects on CSF PD biomarker endpoints, including CSF cGMP, if data permit

To explore the relationship between the E2027 PD effects (including CSF cGMP) with 
E2027 effects on various efficacy endpoints, if data permit

To explore collected pharmacogenomic (PGx) samples by investigating heterogeneity in 
clinical features of disease, including differences in baseline characteristics as well as 
response to compound (efficacy, safety and/or absorption, distribution, metabolism, and 
excretion [ADME]).  These exploratory analyses are not limited to this protocol or project.  
These findings may be used for identification and validation of new drug targets.
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study in 
subjects with dementia with Lewy bodies (DLB) who will be treated with placebo or a dose of 
E2027 (50 mg QD) for 12 weeks.  An overview of the study design is presented in Figure 1.


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In some of the countries selected for this study, donepezil is approved for DLB, with AChEI
and increasingly memantine often used as part of standard care in patients with DLB.  
Therefore, the study design allows for add-on therapy to standard of care for DLB, which 
includes AChEI and/or memantine at stable doses, except for any prohibited medications 
specified in this protocol.  Subjects who are not receiving AChEI and/or memantine are also 
eligible, but are not permitted to start such medications during the study.  (revised per 
Amendment 03)  Randomization will be stratified based on whether subjects are on a stabilized 
dose of AChEI or not and by geographical region (ie, North America, Europe, Japan).  Up to 
approximately 20% of randomized subjects will be on memantine.  (revised per 
Amendment 04)  Subjects will be randomized to placebo and a dose of E2027 (50 mg QD) in 
a ratio of 1:1.
For all subjects study participation will comprise 2 phases:  Prerandomization and 
Randomization.  The Prerandomization Phase will last for up to 6 weeks and will include a 
Screening Period (up to 5 weeks) and a Baseline Period (1 week).  The Randomization Phase 
will last for 16 weeks and will include a Treatment Period (12 weeks) and a Follow-up Period 
(4 weeks).  
Figure 1
Study Design for Study E2027-G000-201
*Subjects will have follow-up 4 weeks after the end of the treatment and a final assessment completed.
R = randomization
9.1.1
Screening Period
Screening will occur between Day -42 and Day -8.  The purpose of the Screening 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 subject and before the conduct of any 
Period:
Screening
Baseline
R
E2027 50 mg
Day -42 to -8
Day 1
4 weeks after the last 
dose of study drug
Placebo
12 weeks
Phase:
Randomization
Prerandomization
Follow-Up*
Double-Blind Treatment


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screening procedures or assessments.  All subjects will be assessed for eligibility through 
review of medical history, physical examination (including neurological examination),
laboratory tests, vital signs and electrocardiograms (ECGs).  They will be assessed on clinical 
scales of cognition and depression, safety magnetic resonance imaging (MRI of the brain) and 
dopamine transporter (DAT)
brain imaging or myocardial scintigraphy ([123I]meta-
iodobenzylguanidine [MIBG]) (if indicated in individual subjects and not previously 
performed) to confirm that they meet the diagnostic criteria and severity for DLB.  Their motor 
features will be assessed on the Movement Disorders Society (MDS) Unified Parkinson’s 
Disease Rating Scale Part III:  Motor Examination (UPDRS-III) and staged by the Hoehn and 
Yahr Scale (HYS).  Their history of suicidality will be assessed by the Columbia Suicide 
Severity Rating Scale (C-SSRS).  They will also be assessed regarding other medical 
conditions and concomitant medications to ensure that these are stable with no changes to 
treatment required and that they do not interfere with their safety or study procedures.
Eligibility assessments at Screening will be conducted in tiers and subjects will need to satisfy 
eligibility criteria in each tier before proceeding to the next tier.  In Tier 1 demographics, 
medical history (including history of DLB and other medical conditions) and concomitant 
medications will be reviewed.  In Tier 2, clinical assessments on cognition and depression will 
be conducted in the morning (whenever possible) in subjects in the following order:  MMSE 
and Geriatric Depression Scale (GDS) should be done first, followed by the MoCA and 
SCOPA-Sleep.  The caregivers or informants will also complete the Short Fluctuation 
Questionnaire (SFQ), CFI and the NPI.  If the eligibility criteria regarding the MMSE and GDS 
are not met, the other procedures (MoCA, SCOPA-Sleep, SFQ, CFI and NPI) do not have to 
be performed and the subject should be screen failed.  In Tier 3 subjects will be assessed with 
the Modified Hachinski Ischemic Scale, UPDRS-III, HYS and C-SSRS.  In Tier 4 subjects 
will undertake physical examination, vital signs, ECG and clinical laboratory tests.  In Tier 5, 
subjects will be assessed by safety MRI for brain abnormalities that may affect eligibility.  In 
Tier 6, if indicated as judged by the investigator, individual subjects may also undertake DAT
brain imaging scan or myocardial MIBG scan to help establish their diagnosis.  It is 
recommended that where appropriate Tiers 1 to 4 should be performed on the same day and 
Tiers 5 and 6 on a separate day.  However, the investigator may perform the various tiers on 
separate days as appropriate for each subject.  The scores of various clinical scales (including 
NPI, SFQ, and UPDRS-III) and cognitive tests (MMSE, MoCA) at Screening will be reviewed 
by a central process.  Subjects who are diagnosed by the investigator with DLB but whose 
scores on clinical scales or cognitive tests are found not to be consistent with the diagnosis 
during central review will be discussed with the investigator to determine their eligibility.  
Due to the intrinsic variability of cognitive functions in DLB, subjects who screen fail at Tier 2 
may be rescreened after at least 30 days, but as a guide, rescreening frequency should not be
more frequent than once every 4 months and a subject should not be rescreened more than 
2 times under the same version of the eligibility criteria.  Subjects who are deemed eligible 
after passing all tiers at Screening will proceed to the Baseline Visit.


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9.1.2
Baseline Period
The Baseline Visit may take place at any time up to 7 days before the first dose of study drug 
(Day 1, ie, during Day -7 to Day -1, but should take place at least 2 weeks after the Screening 
Visit Tier 2 assessments).  In subjects who had DAT brain imaging scan or MIBG scan during 
Screening, the Baseline Visit must take place at least 1 week after the scan.  Study assessments 
should be conducted in the morning (whenever possible).  Cognition will be assessed by the 
MoCA, which should be the first clinical scale to be administered before any invasive 
procedures.  It is recommended that after the MoCA the following efficacy assessments in 
subjects should be performed in the following overall order (other study assessments may be 
conducted in between these efficacy assessments):  Clinician Interview Based Impression of 
Severity plus Caregiver Input (CIBIS-Plus) and SCOPA-Sleep.  The subject will be 
interviewed to complete the DEMQOL.  The EQ-5D will be self-administered and completed 
by the subject.  The caregiver or informant will also complete the CIBIS-Plus, NPI, CFI, EQ-
5D Proxy Version 1 and will be interviewed to complete the DEMQOL-Proxy.  The rater 
administering the CIBIS-Plus should be independent of the rater(s) who administer the other 
clinical scales.  
At Baseline Visit subjects will be assessed regarding other medical conditions and concomitant 
medications (including medications for DLB) to ensure that these remain stable with no 
changes to treatment required and that they do not interfere with their safety or study 
procedures.  Other safety assessment including vital signs, ECGs, laboratory tests and C-SSRS
will also be conducted.  The results of clinical laboratory tests at the Baseline Visit must be 
reviewed by the investigator in accordance with Exclusion Criterion 17 before proceeding to 
randomization, unless these tests showed no clinically significant out of range values at 
Screening.
9.1.3
Randomization Phase/Treatment Period
After completing study assessments at the Baseline Visit, subjects who continue to be eligible 
will proceed to the Randomization Phase, and will be randomized to placebo or E2027 (50 mg 
QD).  They will be provided with study drug (placebo or E2027) to start administration in the 
morning of Day 1 at home.  They will continue to take study drug for 12 weeks.  During the 
Treatment Period study visits will be conducted after 2, 4, 6, 9 and 12 weeks on study drug.  
Safety assessments will be conducted at all these visits.  Efficacy assessments will be 
performed after 6 and 12 weeks on study drug and should be performed at approximately the 
same time of the day as at the Baseline Visit whenever possible (preferably in the morning).  
The MoCA should be the first clinical scale to be administered before any invasive procedures.  
As far as is possible a subject should have the same rater administering the MoCA throughout 
his/her participation in the study.  It is recommended that other efficacy assessments in subjects 
should be performed in the following overall order (other study assessments may be conducted 
in between these efficacy assessments):  CIBIC-Plus, MMSE (after 12 weeks only) and
SCOPA-Sleep.  As far as is possible a subject should have the same rater administering the 
CIBIS/C-Plus throughout his/her participation in the study.  The rater administering the CIBIC-
Plus should be independent of the rater(s) who administer the other clinical scales.  The subject 
will self-complete the EQ-5D.  The caregiver or informant will also complete the CIBIC-Plus, 


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NPI, CFI, and EQ-5D Proxy Version 1.  In addition at the study visit after 12 weeks on study
drug interviews with the subject and the caregiver or informant will be conducted to complete 
the DEMQOL (subject) and DEMQOL-Proxy (caregiver or informant).  Safety assessments 
will be conducted at these visits, including review of adverse events (AEs), vital signs, ECG, 
laboratory safety tests, C-SSRS and UPDRS-III.  The investigator will review all the efficacy 
endpoints and safety data at the visits after 6 weeks and 12 weeks on study drug and formulate 
the CGIC-DLB of the subject’s clinical status from Baseline.  
9.1.3.1
CSF Substudy
A subset of subjects will participate in a substudy in which CSF will be collected by LP during 
Screening and again during the Randomization Phase after 9 weeks of treatment on study drug.  
Participation in the substudy will be voluntary.  After they have completed all screening 
assessments and are deemed eligible for the study, a baseline CSF sample will be collected at 
least 7 days before the Baseline Visit.  If necessary, in these subjects the Screening Period may 
be extended by 1 week after discussion with the sponsor medical monitor.  After they have 
completed 9 weeks of treatment, they will have a 2nd CSF sample collected.  The CSF samples 
will be collected in the morning at approximately the same time, either in the fasted state
(preferred) or at least 2 hours after breakfast.
As data permit, CSF cGMP will be assayed to evaluate the PD effects of E2027 in these 
subjects with DLB.  Other CSF PD biomarkers related to DLB or E2027 PD effects may also 
be assayed if appropriate.  CSF E2027 concentrations will also be determined.
9.1.4
Follow-Up Period
After the Treatment Period, subjects will undertake a Follow-Up Visit 4 weeks after the final 
dose of study drug.  Efficacy assessments should be performed at approximately the same time 
of the day as at the Baseline Visit whenever possible (preferably in the morning).  The MoCA 
should be the first clinical scale to be administered before any invasive procedures.  It is 
recommended that other efficacy assessments in subjects should be performed in the following 
overall order (other study assessments may be conducted in between these efficacy 
assessments):  MMSE and SCOPA-Sleep.  The caregiver or informant will also complete the 
CFI and NPI.  Safety assessments will also be completed.  
The end of study is defined as the last subject completing the Follow-Up Visit.
Subjects who prematurely discontinue study drug for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  The safety and 
efficacy assessments normally performed after 12 weeks of treatment will be conducted at the 
ED Visit.  In addition, subjects who discontinue study drug are expected to continue in the 
study for the originally scheduled visits, starting with the next such visit that is >7 days after 
the ED Visit.  Subjects who prematurely discontinue the study should attend at least 1 
originally scheduled visit after the ED Visit.


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9.1.5
Data Safety Monitoring Board
An independent data safety monitoring board (DSMB) will convene at regular intervals to 
monitor the overall safety of the study and to make recommendations to the sponsor related to 
study safety as appropriate.  The DSMB will be asked to review the cumulative safety data up 
to the date identified to make a determination if the study is safe to proceed unchanged or to 
provide recommendations to the sponsor as to how to proceed.  The study will proceed, 
including randomization of additional subjects, during DSMB safety reviews.  Details will be 
provided in the DSMB Charter.
9.2
Discussion of Study Design, Including Choice of Control Groups
This is randomized, double-blind, placebo-controlled POC study to evaluate the efficacy and 
safety of E2027 in subjects with DLB.  Randomization will be used to avoid bias in the 
assignment of subjects to treatments.  Stratification will be used to ensure that baseline 
characteristics which may affect treatment response (whether subjects are established on 
AChEI or not and by region) are balanced across treatment groups and to ensure the validity 
of statistical comparisons across treatment groups.  Blinding to treatment will be used to reduce 
bias during evaluation of efficacy and safety endpoints.
This study selects DLB within the LBD spectrum for the following reasons:  (1) as the first 
POC study having only DLB subjects, it ensures a relatively more homogeneous population 
and reduces variability compared to having a broad mixture of DLB and PDD subjects, which 
optimizes the probability of detecting cognitive efficacy; (2) DLB subjects have higher 
incidence of concomitant amyloid pathology similar to AD and therefore may have similar 
changes in the cGMP pathways as in AD, so the pharmacological mechanism of E2027 may 
be more likely to show efficacy in DLB, making DLB more attractive for this stage of clinical 
development.  
A meta-analysis of efficacy in clinical trials of AChEI in PDD and DLB suggested comparable 
efficacy effect size in both diagnostic categories (Matsunaga, et al., 2015), which makes it 
plausible that a new drug with efficacy in DLB may also be efficacious in PDD (or vice versa).  
Therefore, if E2027 is efficacious in DLB in Study 201 it will support extending its indications 
to PDD in the LBD spectrum in phase 3 clinical development.
AChEIs are the current standard treatments for LBD (Walker, et al., 2015; McKeith, et al.,
2017; UK National Institute for Health and Care Excellence [NICE] guideline, 2018); as such, 
subjects who are established on a stable dose of AChEIs are eligible.  There is also some 
evidence of overall clinical benefit of memantine in treatment of DLB although the benefit on 
cognition was small (Aarsland, et al., 2009), and increasingly it is also used as part of standard 
treatment in some national guidelines (eg, UK NICE guideline, 2018).  As not all subjects will 
receive AChEI and/or memantine as standard care, subjects who are naïve to AChEI or 
memantine are also eligible.  Studies in animal models indicate that E2027 may improve 
cognition either as monotherapy or in combination with an AChEI or memantine.  This 
supports the enrollment of subjects with or without concomitant AChEI and/or memantine 
treatment.  Previous studies showed that the efficacy of rivastigmine or donepezil in PDD or 


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DLB reached maximum effect after at least 12 weeks of treatment (Dubois, et al., 2012; Mori,
et al., 2012).  Similarly, previous studies with memantine suggested some efficacy on global 
clinical endpoints after 12 weeks of treatment (Aarsland, et al., 2009).  Therefore, all subjects 
who are already taking AChEIs or memantine will be required to be on a stable dose for at 
least 12 weeks before Screening.  The design of Study 201 which permits subjects with/without 
concomitant use of AChEI was also used in a previous study with memantine in subjects with 
LBD (Aarsland, et al., 2009).  (revised per Amendment 03)  
Previous studies showed that AChEIs demonstrated efficacy in PDD or DLB after 12 weeks 
of treatment.  It is considered that this is a reasonable clinical expectation for onset of efficacy 
and therefore the treatment duration is set to 12 weeks in Study 201. 
Subjects are diagnosed with DLB as per the 4th report of the DLB Consortium (McKeith, et 
al., 2017), which is recommended by EMA guidelines.  In previous studies of donepezil in 
DLB conducted by Eisai, it was found that subjects with visual hallucinations at baseline 
showed better efficacy. 
Therefore, in this study subjects are required to have visual 
hallucinations to be eligible.
There are 2 coprimary endpoints which include a cognitive endpoint and a global clinical 
endpoint as recommended by regulatory guidelines for clinical trials on dementia.  The primary 
endpoint on cognition is the MoCA, which is a composite cognitive endpoint evaluating 
various domains including attention, memory, executive function and visuospatial abilities.  It
has greater emphasis on executive functions, attention and visuospatial abilities known to be 
impaired in DLB and PDD (Biundo, et al., 2016) than MMSE.  MoCA is less likely to show 
ceiling effect and is more sensitive in detecting early cognitive change in DLB than MMSE 
(Biundo et al., 2016).  It showed similar rate of cognitive decline with MMSE in 1-year follow-
up of DLB patients (Biundo et al., 2016).  Moreover, it showed treatment benefit on cognition 
in a clinical trial of rivastigmine in PDD, indicating sensitivity to treatment effects of cognitive 
enhancing drugs (Li, et al., 2015).  The coprimary endpoint on global clinical status is the 
CIBIC-Plus which evaluates global clinical impression of change from baseline by an 
independent rater who determines change in clinical status solely based on interview with the 
subject and caregiver or informant without reviewing efficacy and safety data obtained 
postrandomization.  It showed overall clinical benefit in subjects treated with donepezil with 
PDD (Dubois, et al., 2012) and DLB (Mori, et al., 2012).  The use of both coprimary endpoints 
(one on cognition and one on global clinical status) is consistent with regulatory guidelines for 
clinical trials in dementia such that if E2027 shows positive results on both coprimary 
endpoints, the study may be considered as a pivotal study in future regulatory submissions.  
Thus, in this study E2027 (50 mg QD) has to show statistically significant benefit on both the 
MoCA and the CIBIC-Plus for E2027 compared to placebo.  If this is not achieved, but E2027 
(50 mg QD) shows statistically significant benefit on at least the MoCA, then the result is 
considered positive for POC, but not a positive pivotal study, and additional pivotal studies 
will be conducted.  
Other cognitive endpoints, including MMSE and CFI, are secondary endpoints.  The MMSE 
is commonly used in clinical practice to document subjects’ cognitive status and showed 
efficacy with donepezil in PDD (Dubois, et al., 2012) and DLB (Mori, et al., 2012; Ikeda, et 


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al., 2015).  The use of MMSE as a secondary efficacy endpoint on cognition allows 
benchmarking of the efficacy of E2027 with other precognitive drugs in these indications.  The 
CFI evaluates within subject fluctuation of cognitive symptoms and it showed treatment 
benefit with donepezil in subjects with DLB (Mori, et al, 2012).  
The NPI evaluates behavioral and psychiatric features in subjects with dementia and it showed 
benefit in subjects treated with rivastigmine in PDD (Burn, et al., 2006) and in subjects treated 
with donepezil in DLB (McKeith, et al., 2000; Mori, et al., 2012).  It is therefore used as one 
of the secondary efficacy endpoints in Study 201 to evaluate efficacy on non-cognitive 
features.  
Sleep disturbance is common in PDD and DLB (Boddy et al, 2007).  The effects of E2027 on 
sleep in animal models were not specifically evaluated.  In Study 201 the effects of E2027 on 
sleep will be evaluated with the Scales for Outcome in Parkinson’s disease—Sleep (SCOPA-
Sleep) which will be an exploratory efficacy endpoint.  This scale showed improvement in 
sleep quality in subjects with Parkinson’s disease psychosis who were treated with 
pimavanserin (Cummings, et al., 2014).  
The CGIC-DLB provides an overall clinician-determined summary measure of change from 
the subject’s clinical status at Baseline Visit that takes into account all available information 
from the efficacy endpoints above (which include cognitive function, non-cognitive symptoms, 
behaviour and the impact of the symptoms on the patient’s ability to function) and safety data. 
The CGIC-DLB is scored by the investigator and is separate from the evaluation with the 
CIBIC-Plus by an independent rater. A similar CGIC endpoint was used in a previous study 
in subjects with AD (Grove, et al., 2014).
9.3
Selection of Study Population
Approximately 260 subjects will be screened to provide a maximum of 182 randomized 
subjects.  Allowing for a 12% dropout rate, it is anticipated that 160 randomized subjects will 
complete the study.  Subjects will be enrolled at approximately 70 sites in North America, 
Europe, and Japan.
Participation in the CSF substudy is voluntary. It is estimated that approximately 30% of 
subjects will participate in the CSF substudy.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Male or female, age 50 to 85 years, inclusive at time of consent.
2. Meet criteria for probable DLB (as defined by the 4th report of the DLB Consortium 
[McKeith, et al., 2017]) (Appendix 1). Specific situations regarding the use the imaging 
are described below:


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a.
have 1 core clinical feature only by the investigator and who did not have previous 
reports of DAT brain imaging scan, MIBG scan or polysomnography (PSG) will 
undertake DAT brain imaging scan or MIBG scan as organized by the investigator.  
b.
have 2 or more core clinical features by the investigator but who are judged as having 
only 1 core clinical feature by central reviewer and who did not have previous reports 
of DAT brain imaging scan, MIBG scan or PSG may undertake DAT brain imaging 
scan or MIBG scan after discussion with the sponsor medical monitor.
c.
have 2 or more core clinical features by the investigator and the central reviewer and 
who did not have previous reports of DAT brain imaging scan, MIBG scan or PSG may 
undertake DAT brain imaging scan or MIBG scan after discussion with the sponsor 
medical monitor if the investigator considers that imaging is necessary to confirm the 
diagnosis.
Where there are local/national regulatory requirements for additional central regulatory 
review of radiation exposure for the use of DAT / MIBG scans, enrollment of subjects 
is restricted to those who do not require a new DAT / MIBG scan conducted under this 
study (ie, subjects who have historical DAT/MIBG scan/PSG results, or subjects who 
have 2 core clinical features of DLB) until such approval is granted by the regulatory 
authority on radiation exposure. Thereafter enrollment of subjects will extend to those 
who may require a new DAT / MIBG scan under this study.  (revised per 
Amendment 01)
3. MMSE >14 and <26 at Screening Visit.
4. Has experienced visual hallucinations during the past 4 weeks before Screening Visit.
5. If receiving AChEIs, must have been on a stable dose for at least 12 weeks before 
Screening Visit, with no plans for dose adjustment during the study.  Treatment-naïve 
subjects can be entered into the study but there should be no plans to initiate treatment with 
AChEIs from Screening to the end of the study.
6. If receiving memantine, must have been on a stable dose for at least 12 weeks before 
Screening Visit, with no plans for dose adjustment during the study.  Treatment naïve 
subjects can be entered into the study but there should be no plans to initiate treatment with 
memantine from Screening to the end of the study.  (revised per Amendment 03)
7. Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the 
opinion of the investigator, not be suffering from cognitive impairment, be sufficiently 
familiar with the subject and spend sufficient time with the subject on a regular basis such 
that the caregiver or informant can reliably fulfill the study requirements and must provide 
separate written consent.  The caregiver or informant should normally be residing with the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has 
to be satisfied that the subject can contact the caregiver or informant readily during the 
times when the caregiver or informant is not with the subject.  As a guide the caregiver or 
informant should have contact with the subject on at least 4 days a week and each day for 
a total of at least 5 hours.  If in doubt about whether a subject's care arrangements are 
suitable for inclusion, the investigator should discuss this with the medical monitor.  At all 
visits caregivers or informants need to attend the visit in person along with the subject.  If 


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during the study, the designated caregiver or informant relinquishes his/her responsibilities 
as caregiver, a replacement caregiver or informant who meets the criteria above and who 
has similar knowledge of the subject’s clinical status from Baseline throughout the 
Treatment Period must be found.  If no such replacement caregiver or informant is 
available, the subject must be discontinued from the study.
8. Provide written informed consent.  If a subject lacks capacity to consent in the investigator's 
opinion, the subject's assent should be obtained, as required in accordance with local laws, 
regulations and customs, plus the written informed consent of a legal representative should 
be obtained (capacity to consent and definition of legal representative should be determined 
in accordance with applicable local laws and regulations). In countries where local laws, 
regulations and customs do not permit subjects who lack capacity to consent to participate 
in this study, they will not be enrolled (revised per Amendment 02).
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond those caused by the subject’s DLB, including any comorbidities detected by 
clinical assessment or MRI.
2. History of transient ischemic attacks or stroke within 12 months of Screening.
3. Modified Hachinski Ischemic Scale >4.
4. Parkinsonian (extrapyramidal) features with Hoehn & Yahr stage IV or higher.
5. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder and current 
major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders 
Fifth Edition (DSM-V).
6. GDS score >8.
7. Severe visual or hearing impairment that may interfere with the subject study assessments 
including cognitive testing.
8. History of deep brain stimulation or other neurosurgical procedure for Parkinson’s disease.
9. Have thyroid stimulating hormone (TSH) above normal range.  Other tests of thyroid 
function with results outside the normal range should only be exclusionary if they are 
considered clinically significant by the investigator.  This applies to all subjects whether or 
not they are taking thyroid supplements.
10. Abnormally low serum Vitamin B12 levels (less than the lower limit of normal [LLN]) for 
the testing laboratory (if subject is taking Vitamin B12 injections, level should be at or 
above the LLN for the testing laboratory).
11. Contraindications to MRI scanning, 
including cardiac pacemaker/defibrillator, 
ferromagnetic metal implants (eg, in skull and cardiac devices other than those approved 
as safe for use in MRI scanners).  Subjects who require sedation for MRI or positron 
emission tomography (PET) scanning as per local guidelines need not be excluded.
12. Evidence of other clinically significant lesions that suggest a dementia diagnosis other than 
DLB on brain MRI at Screening.  All MRIs will be acquired using a standardized procedure 


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that will be outlined in the Imaging Charter and Imaging Acquisition Guidelines (IAG) and 
will be read by an approved centralized reader.
13. Other significant pathological findings on brain MRI at Screening, including but not 
limited to:  any macrohemorrhage (greater than 10 mm at greatest diameter); an area of 
superficial siderosis; evidence of cerebral contusion, encephalomalacia, aneurysms, 
arteriovenous malformations, or infective lesions; evidence of multiple lacunar infarcts or 
stroke involving a major vascular territory, severe small vessel or white matter disease; 
space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or 
arachnoid cysts and less than or equal to 1 cm at their greatest diameter need not be 
exclusionary)
14. Hypersensitivity to E2027 or any of the excipients.
15. A prolonged QTcF as demonstrated by triplicate ECG at the Screening or Baseline Visit
(ie, mean value >450 msec).
16. Had symptomatic orthostatic hypotension or symptomatic orthostatic tachycardia which 
resulted in hospitalization or urgent medical review in hospital in the past 12 months before 
Screening.
17. Any other clinically significant abnormalities which in the opinion of the investigator, 
require further investigation or treatment or which may interfere with study procedures or 
safety in the following:  

Physical examination, ECG, vital signs at Screening or Baseline Visit

Laboratory tests at Screening Visit
18. Malignant neoplasms within 3 years of Screening (except for basal or squamous cell 
carcinoma of the skin, or localized prostate cancer in male subjects).  Subjects who had 
malignant neoplasms but who have had at least 3 years of documented uninterrupted 
remission before Screening need not be excluded.
19. Has a “yes” answer to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior 
assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has 
been hospitalized or treated for suicidal behavior in the past 5 years before Screening.  
20. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the opinion 
of the investigator, this is due to the subject taking prior/concomitant medications for a 
medical condition that is not exclusionary and not due to drug abuse.
21. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) 
which are not stably and adequately controlled, or which in the opinion of the investigator
may affect the subject’s safety or interfere with the study assessments.
22. Taking any of the prohibited medications or not meeting the requirements regarding stable 
doses of permitted medications.
23. Participation in a clinical study involving any investigational drug/device for DLB within 
6 months before Screening or any other investigational drug/device in the 8 weeks or 
5 half-lives (whichever is longer) of the study medication before Screening unless it can 
be documented that the subject was in a placebo treatment arm.


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24. Planned surgery which requires general, spinal or epidural anesthesia that will take place 
during the study.  Planned surgery that requires only local anesthesia and can be undertaken 
as a day case without inpatient stay postoperatively need not result in exclusion if in the 
opinion of the investigator this operation does not interfere with study procedures and 
subject safety.
25. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  
A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug.
26. Females of childbearing potential (NOTE:  All females will be considered to be of 
childbearing potential unless they are postmenopausal [amenorrheic for at least 
12 consecutive months, in the appropriate age group, and without other known or suspected 
cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
27. For subjects who participate in the CSF substudy, the following exclusions apply:  
A bleeding disorder that is not under adequate control (including a plate count 
<50,000, international normalized ratio [INR] >1.5 or partial thromboplastin time 
[PTT] > upper limit of normal [ULN]).
Any contraindications to lumbar puncture (LP) (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, or obesity to the 
extent that it makes LP technically difficult).
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
A subject who discontinues study treatment should be followed for subsequent protocol-
specified visits and procedures.  If a subject discontinues study drug(s) but remains in the study, 
the set of end-of-treatment procedures will be administered, and follow-up information will be 
collected.  The primary reason for discontinuation and all other reason(s) contributing to the 
subject’s discontinuation from study drug(s) should be collected.  If a subject discontinues 
study treatment and the study at the same time, the end-of-study procedures (Final Visit) will 
be followed (see Section 9.5.5).
9.4
Treatment(s)
9.4.1
Treatments Administered
The following treatments will be administered to subjects in this study (Table 4).


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Table 4
Treatments Administered
Drug Name
Strength
Oral Dose Form
Number Dispensed and Frequency
Duration
E2027
25 mg
capsules
2 × 25 mg capsule QD
12 weeks
Placebo
N/A
E2027-matched 
capsules
2 × E2027-matched placebo capsule 
QD
12 weeks
N/A = not applicable, QD = once daily.
9.4.2
Identity of Investigational Product(s)
Test drug and placebo will be supplied by the sponsor in labeled containers.
9.4.2.1
Chemical Name, Structural Formula of E2027

Test drug code:  E2027

Generic name:  not applicable

Chemical name:  7-(2-Methoxy-3,5-dimethylpyridin-4-yl)-1-[(3S)-tetrahydrofuran-3-yl]-
1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one maleate (International Union of Pure and 
Applied Chemistry [IUPAC])

Molecular formula:  C22H22N4O3∙C4H4O4

Molecular weight:  506.52 (390.44, free base)
9.4.2.2
Comparator Drug
Subjects will not receive an active comparator study drug.  An inactive placebo will be used, 
with all subjects maintaining their current standard of care.
9.4.2.3
Labeling for Study Drug
E2027 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language for each of those countries.  
The following information will be provided:

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Storage and handling instructions for E2027 capsules and the placebo capsules are provided 
on the investigational product labels


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9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization scheme 
that will be reviewed and approved by an independent statistician.  The randomization scheme 
and identification for each subject will be included in the final clinical study report for this 
study.
9.4.4
Selection of Doses in the Study
Based on animal cognition models, a sustained increase of CSF cGMP from baseline by 150% 
or higher after dosing to steady state is thought to be required for clinical efficacy, which is 
therefore regarded as a minimum target PD effect required of the doses in this study. In the 
Pfizer Phase 2 monotherapy study of a PDE9 inhibitor (PF-04447943), it was estimated that it 
would achieve a maximal ~100% increase in CSF cGMP from baseline at steady state, but the 
study showed no significant efficacy in AD subjects.  Thus, the level of CSF cGMP elevation 
above 100% required for cognitive improvement in AD or LBD patients is unknown.  
Therefore, in this clinical efficacy POC study, it is important to investigate the procognitive 
effects of a E2027 dose that results in a higher of CSF cGMP elevation from baseline at >150%.
In the MAD study (Study 002) in healthy subjects (aged 50 to 85), the safety, tolerability, PK,
and PD effects of E2027 on CSF cGMP were investigated at 25, 50, 100, 200 and 400 mg QD 
× 14 days.  Mean CSF cGMP % increase from baseline at trough (predose) steady state (Amin,ss) 
and mean E2027 PK parameters for the various doses are shown in Table 1.  The dose-PD
response relationship appears to saturate at 50 mg QD so higher doses do not appear to offer a 
higher probability of efficacy.  Consequently, it is proposed that the dose in Study 201 should 
be 50 mg QD, at which CSF cGMP elevation from baseline was ~200% and higher than the 
minimum level associated with procognitive effects in animal models.  In principle PK/PD 
modelling suggests that a lower dose of ~ 20 mg QD has mean CSF cGMP elevation from 
baseline of ~150% but given the variability of the CSF PD response, such a lower dose will 
have some overlap in its distribution of CSF PD effects with the 50 mg QD dose. This makes 
it less likely for differentiation of clinical efficacy from the 50 mg QD dose. Therefore, as 
Study 201 is the first efficacy study in the target patient population, a lower dose is not 
included. The dose-efficacy relationship will be evaluated later during clinical development, 
if the 50 mg QD dose is shown to be efficacious.  
All doses investigated to date were well-tolerated with no clinically significant safety findings 
in vital signs, ECG intervals, or laboratory tests.
9.4.5
Selection and Timing of Dose for Each Subject
E2027 is administered orally, QD, in the morning with or without food.  Study treatment will 
begin on Day 1 following randomization and treatment will continue for 12 weeks.  Subjects 
should withhold administration of study drug in the morning of the study visit days that blood 
will be drawn in the clinic for PK analysis (Table 6).  Subjects will be instructed to take their 
other concomitant medications at the usual time.


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9.4.6
Blinding
During the Randomization 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 (eg, Eisai Global Safety) until the time of unblinding, per standard operating procedure 
(SOP).
A master list of all treatments and the subject numbers associated with them will be maintained 
in a sealed envelope by the clinical supply vendor, the interactive voice and web response 
system (IxRS) vendor, and the sponsor.  In the event that emergency conditions require 
knowledge of the study treatment given, the blind may be broken via the code breaker facility 
within the IxRS.  Emergency procedures for revealing drug codes are given in Section 9.5.4.5.  
It is solely the investigator’s responsibility in an emergency to decide if breaking the code is 
necessary based on clinical judgement. (revised per Amendment 02)
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study starting at the date of informed consent will be recorded.  The adverse 
event or medical condition for which the concomitant medication or therapy was administered 
will be recorded.
9.4.7.1
Drug-Drug Interactions
Instructions for use of medications that may interact with E2027 are described in 
Section 9.4.7.2.
9.4.7.2
Prohibited and Restricted Concomitant Therapies and Drugs
Unless otherwise specified, the following medications are prohibited from a period of 14 days 
(or 5 half-lives, whichever is longer) before the Baseline Visit (Visit 2) until the Follow-Up 
Visit to avoid the risk of interaction with E2027.  Subjects who start any of these medications 
during the study will be discontinued.

Drugs known to be strong inhibitors of cytochrome P450 (CYP) 3A, which increase 
exposure of drugs that are CYP3A substrates by >5 fold, grapefruit, grapefruit juice, and 
grapefruit products.  

Drugs known to be moderate to strong inducers of CYP3A.  Herbal preparations containing 
St.  John’s Wort is prohibited for 4 weeks before the Baseline Visit (Visit 2) until the 
Follow-Up Visit.  

Drugs known to cause prolongation of the QT interval, including but not limited to drugs 
that may cause cardiac arrhythmias. For drugs that may cause QTcF prolongation, subjects 
need not be excluded, if at Screening subjects are already on stable doses for at least 
4 weeks and their mean QTcF on triplicate ECGs at Screening and Baseline Visit is not 
>450 ms (Exclusion Criterion 15).


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
Drugs that are PDE inhibitors (eg, theophylline, aminophylline, sildenafil, tadalafil, 
vardenafil, dipyridamole, roflumilast, apremilast, inamrinone, milrinone, and enoximone)
The following medications are prohibited to avoid the risk of interference with study 
assessments or procedures.  Subjects who start these medications during the study will be 
discontinued unless otherwise specified.

Anticholinergic drugs that have CNS activity are prohibited from 4 weeks before Screening 
Visit until the Follow-Up Visit.

Pimavanserin is prohibited for 12 weeks before Screening Visit until the Follow-Up Visit.  
(revised per Amendment 03)

In subjects who participate in the CSF substudy only, anticoagulants (eg, heparin, heparin 
derivatives, non-heparin derivatives, warfarin, dabigatran) and dual antiplatelet therapy 
(eg, aspirin and clopidogrel together) are prohibited from Screening Visit until after the 
2nd CSF collection at 9 weeks postrandomization.  These subjects who start anticoagulants 
or dual antiplatelet therapy at any time before CSF collection at 9 weeks postrandomization 
will not participate in the CSF substudy.
The following restrictions apply to AChEIs (including donepezil, rivastigmine, galantamine) 
for treatment of DLB:

If a subject is already receiving AChEI at Screening, then they must be on a stable dose for 
at least 12 weeks before Screening and remain on the same dose during the study until the 
Follow-Up Visit.

If a subject is not already receiving AChEI at Screening, then these should not have been 
used for at least 12 weeks before Screening and AChEI should not be started during the 
study until the Follow-Up Visit.

As far as it is feasible subjects who start AChEI or change their dose of AChEI during the 
study should undertake an Unscheduled Visit before making such changes in their AChEI 
medications to undertake efficacy assessments (MoCA, CIBIC-Plus, MMSE, SCOPA-
Sleep, NPI, CFI, CGIC-DLB) (unless they have been conducted within past 4 weeks).  This 
change in AChEI medication is considered a protocol deviation and the handling of 
efficacy data collected after the change of these medications in the efficacy analyses is 
described in Section 9.7.1.6.  
The following restrictions apply to memantine for treatment of DLB (revised per 
Amendment 03):

If a subject is already receiving memantine at Screening, they must be on a stable dose 
for at least 12 weeks before Screening and remain on the same dose during the study until 
the Follow-Up Visit.

If a subject is not already receiving memantine at Screening, then this should not have 
been used at least 12 weeks before Screening and memantine should not be started during 
the study until the Follow-Up Visit.

As far as it is feasible subjects who start memantine or change their dose of memantine 
during the study should undertake an Unscheduled Visit before making such changes in 
their memantine to undertake efficacy assessments (MoCA, CIBIC-Plus, MMSE, 
SCOPA-Sleep, NPI, CFI, CGIC-DLB) (unless they have been conducted within past 


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4 weeks).  This change in memantine is considered a protocol deviation; the handling of 
efficacy data collected after the change of these medications in the efficacy analyses is 
described in Section 9.7.1.6.
The following restrictions apply to medications for Parkinson’s disease or motor symptoms of 
DLB (except CNS-active anticholinergic drugs that are prohibited as above):

If a subject is already on any of these medications at Screening, then they must be on a 
stable dose for at least 4 weeks before Screening and remain on the same dose during the 
study until the Follow-Up Visit.

If a subject is not already on any of these medications at Screening, then these should not 
be started during the study until the Follow-Up Visit.

Starting or changing the dose of these medications during the study is considered as 
protocol deviation and the handling of efficacy data collected after the change of these 
medications in the efficacy analyses is described in Section 9.7.1.6.
The following restrictions apply to medications for antipsychotic or neuroleptic drugs, Yi Gan 
San, hypnotics, anxiolytics or antidepressants:

If a subject is already on any of these medications at Screening, then they must be on a 
stable dose for at least 4 weeks before Screening and remain on the same dose during the 
study until the Follow-Up Visit.

If a subject is not already on any of these medications at Screening, then these should not 
be started during the study until the Follow-Up Visit.

As far as it is feasible subjects who start or change their dose of these medications should 
undertake an Unscheduled Visit before making such changes in these medications to 
undertake efficacy assessments (MoCA, CIBIC-Plus, MMSE, SCOPA-Sleep, NPI, CFI, 
CGIC-DLB) (unless they have been conducted within past 4 weeks).  This change in such 
medications is a protocol deviation and the handling of efficacy data collected after the 
change of these medications in the efficacy analyses is described in Section 9.7.1.6. 
The following restrictions apply to other medications that the subject is taking at Screening or 
are started during the study:

These medications may be permitted if they are not included in the prohibited or restricted 
medications list above, and are considered by the investigator and sponsor medical monitor 
not to compromise study assessments or subject safety.

Permitted prior medications should be at a stable dose for at least 4 weeks before Screening 
and as far as possible remain on the same dose throughout the study.  

Subjects who change the dose of their permitted prior medications or who start permitted 
new medications during the study may continue in the study if the investigator and sponsor 
medical monitor consider that this will not compromise study assessments or subject safety.  

As needed (PRN) medications required for performing LP for CSF sampling are permitted 
in the CSF substudy.


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9.4.7.3
Other Restrictions
E2027 absorbs light within the range of natural sunlight (290 - 700 nm). This possible effect 
of photosensitive skin reactions has not been fully evaluated in humans. In clinical studies 
conducted with E2027, which included subjects treated with E2027 50 mg QD for 6 weeks, 
there were no reported AEs of skin sensitivity due to exposure to sunlight. 
Until 
photosensitivity is evaluated, subjects are advised to avoid exposure to artificial ultraviolet 
light and excessive or prolonged exposure to sunlight while taking the study drug. (revised 
per Amendment 01)
Male subjects who are currently in the treatment period are required to practice highly effective 
contraception throughout the treatment period and for 98 days after study drug discontinuation 
if they meet both of the following criteria: (1) have not had a successful vasectomy (confirmed 
azoospermia); (2) have female partners of childbearing potential. (revised per Amendment 05)  
Male subjects meeting such criteria but who cannot practice contraception will be discontinued 
from study drug.  
Male subjects who have already discontinued study drug at the time of Amendment 05, but for 
whom less than 98 days have passed since taking their final dose of study drug, are required to 
practice highly effective contraception until 98 days after study drug discontinuation if they 
meet both of the following criteria: (1) have not had a successful vasectomy (confirmed 
azoospermia); (2) have female partners of childbearing potential. 
The following highly effective contraception methods are acceptable:

Total abstinence (if it is their preferred and usual lifestyle)

An intrauterine device or intrauterine hormone-releasing system (IUS)

A contraceptive implant

An oral contraceptive 
-
Female partners of male subjects who are currently in the treatment period must 
be on a stable dose of the same oral contraceptive product for at least 28 days 
before male subject’s dosing and throughout the treatment period and for 98 days 
after study drug discontinuation
-
Female partners of male subjects who have already discontinued study drug at the 
time of Amendment 05 must be on a stable dose of the same oral contraceptive 
product for at least 28 days before the implementation of Amendment 05 and 
continue until 98 days after the male subject’s study drug discontinuation
No sperm donation is permitted throughout the treatment period and for 98 days after study 
drug discontinuation.
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.


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9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided to 
the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the subjects 
to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

Current medical license or proof of qualification of principal investigator (not required for 
sites outside North America if the qualification can be verified by their curriculum vitae)  

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical institution 
or the designated pharmacist) will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and adherence 
to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs 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 all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs 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, and (e) documentation of returns to the 
sponsor.  All forms will be provided by the sponsor.  Any comparable forms that the site wishes 
to use must be approved by the sponsor.


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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 (eg, FDA, 
Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs and 
empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) 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, 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.
9.5
Study Assessments
9.5.1
Assessments
After the subject has provided informed consent, screening assessments will be performed in 
6 tiers as noted in Table 6.  All assessments and procedures in each tier should be completed, 
and eligibility to continue confirmed, before any assessments/procedures from the next tier 
commence.  
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, and ethnicity.  For caregivers or 
informants, their age, sex, relationship to subject, residential status with the subject, and time 
spent per week with the subject will be collected at the Screening Visit.
9.5.1.2
Baseline/Screening Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, prior and concurrent medications including AChEI and 
memantine use, and current medical conditions will be recorded at the Screening Visit.  
(revised per Amendment 03)  All medical and surgical history within 5 years must be noted in 
the Medical History and Current Medical Conditions electronic case report forms (eCRFs). 
Medical history will include history of DLB.  


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Physical examinations will be performed as designated in Table 6.  A complete physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including 
heart and lungs), abdomen, limbs, a dermatologic exam, and a neurologic examination 
(including general status, cranial nerve function, motor system, coordination/cerebellar 
function, reflexes, and sensory system).  A urogenital examination will only be required in the 
presence of clinical symptoms related to this region.  Documentation of the physical 
examination will be included in the source documentation at the site.  Significant findings at 
the Screening Visit will be recorded on the Medical History and Current Medical Conditions 
eCRF.  Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the AE eCRF.  
9.5.1.2.2
OTHER SCREENING/BASELINE ASSESSMENTS
In addition, the following tests will be performed during screening (see Table 6):  GDS, SFQ,
HYS, safety brain MRI, DAT brain imaging and myocardial MIBG scan.
Geriatric Depression Scale (GDS)
This is a self-reported, clinician-assisted scale designed to identify symptoms of depression in 
the elderly.  The scale consists of 15 questions that the subject is asked to answer about how 
they felt over the past week.  Answers to 5 of the items are negatively oriented for depression 
(eg, Do you feel full of energy?) and 10 positively oriented (eg, Do you often feel helpless ?).  
One point is given for each appropriate positive or negative answer indicative of a symptom 
of depression, for a possible total of 15 points.  Total scores of 0 to 5 are considered normal 
and scores of 6 to15 are considered depressed.  Subjects with DLB who have a GDS score >8 
are considered to have significant depressive symptoms which may contribute to cognitive 
deficits and are excluded.
Short Fluctuation Questionnaire (SFQ)
This scale consists of 8 questions as to whether fluctuation occurs in various domains including 
attention, ability to performance daily functions, orientation, verbal communication and 
behavior.  It is scored as 1 for presence of fluctuation in each domain and 0 for absence. It has 
a score range of 0 to 8. Investigators should take into account the SFQ score in deciding if a 
subject meets one of the core criteria (fluctuating cognition) for diagnosis of DLB.
Hoehn and Yahr Scale (HYS)
This scale is used to stage (I to V) the severity of motor features in Parkinson’s disease. It 
captures typical patterns of progressive motor impairment.
It is based on the extent of 
anatomical distribution of the extrapyramidal features (unilateral or bilateral, limbs or limbs 
and trunk) and severity (mild, moderate, severe, loss of mobility). Subjects with Stage IV 
disease (severe disability but still able to walk or stand unassisted) or worse are excluded.  


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Safety Brain MRI
Safety brain MRI will be conducted at Screening to identify various exclusionary lesions and 
other MRI abnormalities which may indicate significant contribution to cognitive impairment 
from non-DLB causes (Section 9.3.2). The MRI settings will be described in the MRI manual 
provided by the central MRI reader, who will also review all MRI scans for eligibility.  
DAT Brain Scan
In this brain scan, an intravenous radiopharmaceutical 123I-ioflupane that selectively binds to 
the striatal dopamine transporter in the brain is administered.  It is used to visualise the levels 
of DAT in the striatum (caudate and putamen) using single-photon emission computed 
tomography (SPECT) brain imaging. In subjects with Parkinsonian syndromes including DLB 
and Parkinson's disease, there is reduced DAT signal in the scan in the striatum (putamen and 
caudate). This pattern may be asymmetrical between left and right sides or there may be 
diffuse reduction on both sides. DAT scans will be evaluated by a central reader. Subjects who 
undertake DAT brain imaging are required to have abnormal (low uptake of 123I-ioflupane) in 
the striatum as 1 of the eligibility criteria. 
MIBG Myocardial Scan 
In this cardiac scan, an intravenous radiopharmaceutical 123I-meta-iodobenzylguanidine
(MIBG) that is selectively taken up via the norepinephrine transporter into the post-ganglionic 
sympathetic nerve terminals in the heart is administered. Uptake into these sympathetic nerve 
terminals is then visualised using single-photon emission computed tomography (SPECT) 
imaging.  In subjects with Parkinsonian syndromes including DLB and Parkinson's disease, 
there is reduced MIBG uptake in the heart such that the ratio of the MIBG signal in the heart 
to the mediastinum is reduced.  MIBG cardiac scans will be evaluated by a central reader. 
Subjects who undertake MIBG cardiac scans are required to have abnormal (low uptake of 
MIBG) in the heart as one of the eligibility criteria. 
For a detailed description of the sequence in which these assessments are administered at 
Screening or Baseline Visit, see Sections 9.1.1 and 9.1.2.
9.5.1.3
Efficacy Assessments
Efficacy assessments are summarized in the following sections.  These assessments should be 
performed at approximately the same time of the day as were done at the Baseline Visit 
whenever possible (preferably in the morning). The MoCA should be the first clinical scale to 
be administered before any invasive procedures. It is recommended that other efficacy 
assessments in subjects should be performed in the following overall order:  CIBIC-Plus,
MMSE (after 12 weeks only) and SCOPA-Sleep.  Other study assessments may be conducted 
in between these efficacy assessments.
For a detailed description of the sequence in which these assessments are administered during 
the Treatment and the Follow-Up Periods, see Sections 9.1.3 and 9.1.4.


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9.5.1.3.1
MONTREAL COGNITIVE ASSESSMENT (MOCA)
The MoCA scale assesses different cognitive domains:  attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation.  It is reported to be useful to characterize global cognitive impairment in DLB.  
The total possible score is 30 points; a score of 26 or above is considered normal.  The MoCA
will be assessed as designated in Table 6. 
9.5.1.3.2
CLINICIAN’S INTERVIEW BASED IMPRESSION OF CHANGE PLUS CAREGIVER INPUT 
(CIBIC-PLUS)
The CIBIC-Plus scale is designed to measure various domains that describe subject function:  
general, mental/cognitive state, behavior, and activities of daily living.  It is a semi-structured 
global rating derived from a comprehensive interview with the subject and caregiver or 
informant by an independent rater who has no access to the source data or other psychometric 
test scores conducted postrandomization as part of the given protocol.
At Baseline (Visit 2), this independent rater will use a related tool, the CIBIS-Plus.  This scale, 
which assesses disease severity on a 7-point scale from 1 = normal to 7 = extremely ill, 
establishes a point of reference for subsequent interviews using the CIBIC-Plus.  
During the Treatment Period, the rater will administer the CIBIC-Plus separately to the subject 
and the caregiver or informant as designated in Table 6.  At the end of each pair of interviews 
during each of these study visits, the rater alone will determine separately for each of the 
4 domains whether the disease has improved, worsened, or remained unchanged since the 
evaluation at Baseline.  The CIBIC-Plus scores are:  1 (marked improvement), 2 (moderate 
improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 6 (moderate 
worsening) and 7 (marked worsening).
The CIBIC-Plus will also be assessed at ED and Unscheduled Visits.
9.5.1.3.3
NEUROPSYCHIATRIC INVENTORY (NPI)
The NPI scale assesses frequency and severity of 12 neuropsychiatric symptoms commonly 
described 
in 
dementia 
patients: 
 
delusions, 
hallucinations, 
agitation/aggression, 
depression/dysphoria, 
anxiety, 
elation/euphoria, 
apathy/indifference, 
disinhibition, 
irritability/lability, motor disturbance, nighttime behaviors and appetite/eating changes.  The 
scale also assesses the degree of caregiver or informant distress engendered by each of the 
symptoms.  It is rated from 0 to 144 with high scores meaning a greater neuropsychiatric 
disturbance.  A subscore covering the domains of delusions, hallucinations, apathy, and 
depression (NPI-4) will also be derived.  
The NPI will be assessed as designated in Table 6.  The caregiver or informant will complete 
the NPI at these visits.


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9.5.1.3.4
MINI-MENTAL STATE EXAMINATION (MMSE)
The MMSE is a 30-point scale that measures orientation to time and place, registration, 
immediate and delayed recall, attention, language, and drawing.  Scores range from 0 (most 
impaired) to 30 (no impairment).  The MMSE will be assessed as designated in Table 6. 
9.5.1.3.5
COGNITIVE FLUCTUATION INVENTORY (CFI)
The CFI scale assesses cognitive fluctuation with the same format as the NPI.  It evaluates 
fluctuation in various domains including attention, ability to performance daily functions, 
orientation, verbal communication and behavior.  It is scored based on frequency and severity 
with a score range of 0 to 12.  The scale also assesses the degree of caregiver or informant 
distress engendered by the symptoms. The CFI will be assessed as designated in Table 6.
9.5.1.3.6
SCALES FOR OUTCOME IN PARKINSON’S DISEASE-SLEEP (SCOPA-SLEEP)
The SCOPA-Sleep includes sections for evaluation of night time and daytime sleep.  There are 
5 questions for night time sleep:  (1) trouble falling asleep, (2) awakening during the night, 
(3) episodes lying awake too long at night, (4) early morning waking and (5) patient’s 
impression whether they had adequate duration of sleep at night.  There are 6 questions for 
daytime sleep, (1) falling asleep unexpectedly during the day or evening, (2) falling asleep 
while sitting peacefully, (3) while watching television or reading, (4) while talking to someone, 
(5) trouble staying awake during the day or evening, and (6) experiencing falling asleep as a 
problem.  The SCOPA-Sleep will be assessed as designated in Table 6.  .
9.5.1.3.7
CLINICIAN GLOBAL IMPRESSION OF CHANGE IN DEMENTIA WITH LEWY BODIES 
(CGIC-DLB)
The CGIC-DLB provides an overall clinician-determined summary measure of change from 
the subject’s clinical status at the Baseline Visit that takes into account all available 
information from the efficacy endpoints above (which include cognitive function, non-
cognitive symptoms, behaviour, and the impact of the symptoms on the subject’s ability to 
function) and safety data. It is to be performed by the investigator and is a separate efficacy 
assessment from the CIBIC-Plus. The CGIC-DLB will be assessed as designated in Table 6. 
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
Collection and handling of PK, PD, and PGx samples will be detailed in the central laboratory 
manual to be provided to clinical sites.  
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of plasma E2027 concentrations for PK
analysis.  Two blood samples for PK will be drawn at Week 2:  at predose (within 30 minutes 
before dosing) and 1 to 3 hours postdose.  Three blood samples for PK will be drawn at Weeks 
6 and 12:  at predose (within 30 minutes before dosing), 1 to 3 hours, and 4 to 8 hours postdose.  
Additionally, 2 blood samples for PK will be drawn at Week 9:  1 at predose (30 minutes before


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dosing), and another at 1 to 4 hours postdose.  At these visits, subjects or their caregivers or 
informants will be instructed not to take their study drug at home on the day the blood samples 
for PK are collected.  Instead, subjects will take their study drug at the clinic after the predose 
blood draw; then a postdose blood draw will be performed.  In addition, subjects or their 
caregivers or informants will be instructed to record the time of study drug administration for 
the 2 days before these visits when self-administered at home and this information will be 
collected and recorded on the eCRF.  
Plasma E2027 concentrations and those of its metabolites (if appropriate) will be measured 
using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay 
methods.
In subjects who participate in the CSF substudy, CSF specimens will be collected for the 
determination of CSF E2027 concentrations as designated in Table 6.  A predose blood sample 
for PK will be taken first, followed by CSF sampling. Subjects will then be administered study drug.
CSF E2027 concentrations and those of its metabolites (if appropriate) will be measured using 
validated LC-MS/MS assay methods.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Pharmacodynamic and Other Biomarker Assessments
In subjects who participate in the CSF substudy, a CSF sample will be collected as specified 
in the Schedule of Procedures/Assessments (Table 6).  Samples should be collected at 
approximately the same time in the morning, either in the fasted state (preferred) or at least 
2 hours after breakfast.  The CSF sample during the Treatment Period should be collected after 
the predose blood draw for PK analysis at the study visit after 9 weeks on study drug, followed 
by study drug administration.  The CSF samples will be assayed for cGMP and E2027. CSF 
cGMP concentrations will be measured using a validated LC-MS/MS assay method. Other 
CSF biomarkers related to DLB or E2027 PD effects may also be assayed if appropriate.  
Pharmacogenomic Assessments
PGx blood samples will be collected as specified in the Schedule of Procedures/Assessments 
(Table 6) where feasible and in accordance with local regulations.  See the Lab Manual for a 
description of collection, handling, and shipping procedures of the samples. Participation in 
PGx assessments is voluntary and subjects must provide a separate informed consent prior to 
blood collection for PGx assessment.
The PGx blood samples may be used to genotype common and rare genetic variants. Data 
obtained from the PGx analysis will be used for research, to assist in developing safer and more 
effective treatments and will not be used to change the diagnosis of the subject or alter the 
therapy of the subject.  The deoxyribonucleic acid (DNA) will not be used to determine or 
predict risks for diseases that an individual subject does not currently have.  Any sample may 
be stored for up to 15 years, based on country specific regulations to assist in any scientific 
research questions related to E2027 or DLB. 


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9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, and monitoring of 
hematology, blood chemistry, and urinalysis values; measurement of vital signs (including 
orthostatic changes), ECGs, the performance of physical examinations; C-SSRS and UPDRS-
III as detailed in Table 6.  A safety brain MRI may also be performed at Unscheduled Visits if 
deemed appropriate by the investigator. 
9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2027.
The criteria for identifying AEs in this study 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 (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is being 
reported as an AE)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, 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, withdrawal of study drug, or withholding of 
study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  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. SAEs will be collected for 28 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.  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.  Any laboratory abnormality considered 
to constitute an AE should be reported on the AE eCRF.  
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.


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It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be classified 
as an AE (see Section 9.5.1.5.8 for a description of the C-SSRS).  
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
The following adverse events will require the collection of information sufficient to provide a 
detailed description of the event, treatment, and outcome to the Medical Monitor for the study:  
fall, syncope, skin rash considered to be related to study drug, and a “yes” answer to Type 4 or 
5 suicidal ideation, or a “yes” response to any suicidal behavior on the C-SSRS.  It is the 
responsibility of the investigator to review the results of the C-SSRS and determine if any 
result constitutes an AE.
If a subject develops a skin rash which is considered by the investigator not to be related to 
study drug, then the study drug should continue. If a subject develops a skin rash that is 
considered by the investigator to be possibly a drug rash related to study drug, the study drug 
should be temporarily stopped and a PK sample should be collected.  The subject should be 
referred to a dermatologist for evaluation.  If it is concluded after dermatologist review that the 
skin rash is not drug rash due to study drug, study drug treatment may be resumed.
If it is concluded after dermatologist review that the skin rash is likely to be a drug rash due to 
study drug, then the study drug should be permanently discontinued if the rash has any of the 
following characteristics:

A bullous rash regardless of severity

A moderate to severe nonbullous rash
If it is concluded after dermatologist review that the skin rash is likely to be a drug rash due to 
study drug, but does not meet the above criteria for discontinuation, then study drug may be 
resumed after the rash has resolved. 
If the rash that is considered by the investigator to be related to study drug but has resolved 
before the dermatologist review then the study drug should be permanently discontinued if the 
rash has any of the following characteristics:

A bullous rash regardless of severity

A moderate to severe nonbullous rash
Otherwise, the study drug may be resumed after the rash has resolved.
AEs that may signal drug abuse potential will require a more detailed follow-up through 
completion of a specific eCRF form.  Similarly, AEs reported during the 28 days following the 
last dose of study drug (Follow-up Period) that might indicate physical dependency also require 


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a more detailed follow-up through completion of the same eCRF form.  This includes AEs that 
fall into the categories listed below.  Examples of such AEs are provided in Appendix 3 and a 
more comprehensive list is provided in the eCRF Completion Guidelines.  This additional 
follow-up of AEs that signal possible drug abuse potential, including physical dependency 
following discontinuation of study drug, is in line with current FDA Guidance for Industry for 
“Assessment for Abuse Potential for Drugs” (FDA 2017 Abuse Potential Guidelines).  As 
neuropsychiatric symptoms are common in DLB, the investigator should exercise clinical 
judgement in deciding if a neuropsychiatric AE [such as those described in Appendix 3] 
constitute an AE of abuse potential.
Euphoria-related terms:

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Dizziness

Thinking abnormal 

Hallucination

Inappropriate affect
Terms indicative of impaired attention, cognition, and mood:

Somnolence

Mood disorders and disturbances
Dissociative/psychotic terms:

Psychosis

Aggression

Confusion and disorientation 

Dissociative state
Related terms not captured elsewhere:

Drug tolerance

Habituation

Substance related disorders
Physical dependence or withdraw (only for events observed within the first 4 weeks 
after the last dose of study drug):

Drug withdrawal syndrome 
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 eCRF.  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
Section 9.5.1.5.2 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
The relationship of each AE to the study drug will be recorded on the eCRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, 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)


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
Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

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, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations 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 special situations are to be reported on the eCRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the 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 after 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 (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
STUDY-SPECIFIC ADVERSE EVENTS
Not applicable.
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 5.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 6) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.


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Table 5
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Coagulationa
INR derived from the prothrombin time, PTT
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, TFTb (TSH, free triidothyronine, and 
free thyroxine), vitamin B12b, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
INR = international normalized ratio, PTT = partial thromboplastin time, RBC = red blood cell, TFT = thyroid 
function test, TSH = thyroid stimulating hormone, WBC = white blood cell.
a:  In subjects who participate in the CSF substudy, a clotting screen (PTT and INR derived from the 
prothrombin time) will be performed.
b:  Screening only.
Clinical laboratory tests during the study will be performed by a central laboratory.  All blood 
and urine samples will be collected and sent to the central laboratory on the day of collection 
unless otherwise instructed.  In cases of a safety concern, blood samples will be split (or
2 samples drawn) to allow a local laboratory analysis in addition to the central laboratory.  
Laboratory certification as available will be included in the final clinical study report for this 
study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 9.5.1.5.1 and the eCRF Completion Guidelines.  In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the AE eCRF.
9.5.1.5.5
VITAL SIGNS, HEIGHT AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, SBP and DBP [mmHg] including orthostatic evaluations, pulse 
[beats per minute], respiratory rate [per minute], body temperature [in centigrade]), height (m),
and weight (kg) will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 6) by a validated method.  Blood pressure and pulse will be 
measured after the subject has been resting for 10 minutes in the supine position. Blood 
pressure and pulse will be measured again after standing up for 2 minutes.  All BP 
measurements should be performed on the same arm, preferably by the same person.  (revised 
per Amendment 01)


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When vital signs are to be obtained concurrently with PK or other blood samples, the vital sign 
measurements will be performed prior to drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
Orthostatic (postural) hypotension will be defined as either asymptomatic orthostatic 
hypotension (change in blood pressure upon standing without lightheadedness) or symptomatic 
orthostatic hypotension (change in blood pressure upon standing accompanied by 
lightheadedness). 
Orthostatic hypotension will be recorded based on the following  criteria:

Drop in systolic BP ≥20 mmHg, or 
Drop in diastolic BP ≥10 mmHg (revised per Amendment 01)
Occurrences of orthostatic hypotension as defined above that also meet any of the following 
criteria are considered clinically significant and will be reported as AEs in this study:

Postural lightheadedness noted upon standing (ie, symptomatic orthostatic 
hypotension)

Requires intervention (eg, resumption of recumbent position, IV fluids, etc.)
Postural lightheadedness upon standing if accompanied by orthostatic BP changes meeting the 
above criteria of orthostatic hypotension should be reported as AE of orthostatic hypotension.   
(revised per Amendment 01)
9.5.1.5.6
PHYSICAL EXAMINATIONS
Complete and brief physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 6).  A complete physical examination will include evaluations 
of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, 
a dermatologic exam, and a neurologic examination (including general status, cranial nerve 
function, motor system, coordination/cerebellar function, reflexes, and sensory system).  A 
urogenital examination will only be required in the presence of clinical symptoms related to 
this region.  Documentation of the physical examinations will be included in the source 
documentation at the site.  Significant findings at the Screening Visit will be recorded on the 
Medical History and Current Medical Conditions eCRF.  Only changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the AE
eCRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 6).  Triplicate ECG will be performed after subject has been resting in the supine 
position for at least 10 minutes.  The mean QTcF and other ECG intervals will be determined.  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see


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Section 9.5.1.5.1) and the eCRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
Columbia Suicide Severity Rating Scale (C-SSRS)
An assessment of suicidality using the C-SSRS will be performed as designated in the Schedule 
of Procedures/Assessments (Table 6).
Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS) 
Part III:  Motor Examination
The MDS UPDRS scale evaluates extrapyramidal features in motor function in Parkinson’s 
disease.  It contains 33 items in 18 categories:  (1) speech, (2) facial expression, (3) rigidity, 
(4) finger tapping, (5) hand movements, (6) supinational and pronation movements of hands, 
(7) toe tapping, (8) leg agility, (9) arising from chair, (10) gait, (11) freezing of gait, (12) 
postural stability, (13) posture, (14) body bradykinesia, (15) postural tremor of hands, (16) 
kinetic tremor of hands, (17) rest tremor  amplitude and (18) constancy of rest tremor.  Each 
item is scored 0 to 4, giving a total score range 0 to 132.  As far as is practical, the motor 
assessments should be made with the subject in the “on” state at each visit and at the same time 
relative to the subject’s last dose of Parkinson’s disease medication (such as L-dopa).  (revised 
per Amendment 01)
9.5.1.6
Other Assessments
9.5.1.6.1
DEMENTIA-RELATED QUALITY OF LIFE AS ASSESSED BY THE DEMENTIA QUALITY OF 
LIFE MEASURE (DEMQOL; INTERVIEW OF SUBJECT) AND DEMENTIA QUALITY OF 
LIFE MEASURE BY PROXY (DEMQOL-PROXY; INTERVIEW OF CAREGIVER ABOUT 
SUBJECT)
The DEMQOL and DEMQOL-Proxy are appropriate for use in subjects with mild-moderate 
dementia (MMSE ≥10).  The DEMQOL is a 28-item scale and DEMQOL-Proxy is a 31-item
scale.  Both are interview administered.  There are 5 domains:  daily activities, health and 
well-being, cognitive functioning, social relationships and self-concept.  All items are given a 
score from 1 to 4 and summed to produce domain scores.  A general quality of life item is 
unscored.  The DEMQOL and DEMQOL-Proxy will be assessed at Baseline (Visit 2) and 
Day 84 (Visit 8).  Should the subject progress to severe dementia during the course of the 
study, only the DEMQOL-Proxy should be administered.
9.5.1.6.2
GENERAL HEALTH STATUS AS ASSESSED BY THE EUROQOL- 5 DIMENSION 
QUESTIONNAIRE (EQ-5D; COMPLETED BY SUBJECT) AND EUROQOL- 5 DIMENSIONS 
QUESTIONNAIRE BY PROXY VERSION 1 (EQ-5D PROXY; CAREGIVER COMPLETION OF 
REPORT ABOUT SUBJECT)
The EQ-5D is a widely used general health state and health utility scale to assess the impact of 
any health intervention on the general quality of life of patients.  The health utility values are 
utilized as weights to life expectancy estimates and ultimately are used in a metric known as 


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an incremental cost effectiveness ratio (ICERs).  ICERs are used by health authorities to make 
key decisions that ultimately impact the relative funding of health interventions across multiple 
therapeutic areas based on their relative cost-effectiveness.  Thus, the EQ-5D is not specifically 
developed for any particular disease to allow this cross-therapeutic comparison.  
The scale consists of 5 specific questions (regarding mobility [walking], self-care [washing 
and dressing], usual activities, pain/discomfort, and anxiety/depression) and 1 overall health 
rating.  The EQ-5D is selected in this study due to its brevity and content.  The EQ-5D-5L 
(5 levels of responses to each of the 5 questions) will be utilized in this study as it allows for a 
more granular assessment of the impact of intervention.  
The proxy EQ-5D version is available as EQ-5D-5L (5 levels of responses to each of the 
5 questions) and will be utilized to assess the caregiver’s or informant’s perspective of the 
subject’s health.  The proxy EQ-5D-5L is available in 2 versions:  Proxy version 1 where the 
caregiver or informant (the proxy) is asked to rate the patient’s health-related quality of life in 
their (the proxy’s) opinion and Proxy version 2 where the caregiver or informant (the proxy) 
is asked to rate how he/she (the proxy) thinks the subject would rate his/her own health-related 
quality of life, if the subject were able to communicate it.  Only Proxy version 1 will be utilized 
in this particular study.  The EQ-5D and EQ-5D-Proxy will be assessed at Baseline (Visit 2) 
and Day 84 (Visit 8).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the schedule of procedures/assessments for the study.


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Table 6
Schedule of Procedures/Assessments in Study E2027-G000-201
Phase
Prerandomization
Randomization
Period
Screening
Baseline
Treatment
Follow-Up
Early 
Discontinuation 
(ED) d
Unscheduled 
e
Visit a
1 b
2 c
3 c
Telephone
4
5
6
7
8
9 
Day
-42 to -8
-7 to -1
1
14
28
42
63
84
112
Weeks elapsed since 
randomization
0
2
4
6
9
12
16
Assessments
Informed consent
X
Informed consent for CSF 
substudy (optional)
X
Inclusion and exclusion 
criteria
X
X
Demographics
X 
(Tier 1)
Medical history
X 
(Tier 1)
History of DLB
X 
(Tier 1)
Prior and concomitant 
medications
X 
(Tier 1)
X
X
X
X
X
X
X
X
X
X
MMSE f,g
X 
(Tier 2)
X
X
X
X
GDS f
X 
(Tier 2)
MoCA f,g
X 
(Tier 2)
X
X
X
X
X
X
SCOPA-Sleep f,g
X 
(Tier 2)
X
X
X
X
X
X
SFQ f
X 
(Tier 2)
CFI f,g
X 
(Tier 2)
X
X
X
X
X
X
NPI f,g
X 
(Tier 2)
X
X
X
X
X
X
CIBIS-Plus g
X


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Table 6
Schedule of Procedures/Assessments in Study E2027-G000-201
Phase
Prerandomization
Randomization
Period
Screening
Baseline
Treatment
Follow-Up
Early 
Discontinuation 
(ED) d
Unscheduled 
e
Visit a
1 b
2 c
3 c
Telephone
4
5
6
7
8
9 
Day
-42 to -8
-7 to -1
1
14
28
42
63
84
112
Weeks elapsed since 
randomization
0
2
4
6
9
12
16
Assessments
CIBIC-Plus g
X
X
X
X
CGIC-DLB
X
X
X
X
DEMQOL-Proxy
X
X
DEMQOL 
X
X
EQ-5D
X
X
EQ-5D Proxy
X
X
Modified Hachinski Ischemic 
Scale
X 
(Tier 3)
UPDRS-III
X 
(Tier 3)
X
X
X
X
HYS
X 
(Tier 3)
C-SSRS
X 
(Tier 3)
X
X
X
X
X
X
X
X
X
Height
X 
(Tier 4)
Weight
X 
(Tier 4)
X
X
X
Vital signs h
X 
(Tier 4)
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X 
(Tier 4)
Brief physical examination
X
X
X
X
X
12-lead ECG i
X 
(Tier 4)
X
X
X
X
X
X
X
X
X
Blood and urine for clinical 
laboratory tests j
X 
(Tier 4)
X j
X
X
X
X


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Table 6
Schedule of Procedures/Assessments in Study E2027-G000-201
Phase
Prerandomization
Randomization
Period
Screening
Baseline
Treatment
Follow-Up
Early 
Discontinuation 
(ED) d
Unscheduled 
e
Visit a
1 b
2 c
3 c
Telephone
4
5
6
7
8
9 
Day
-42 to -8
-7 to -1
1
14
28
42
63
84
112
Weeks elapsed since 
randomization
0
2
4
6
9
12
16
Assessments
Blood for vitamin B12 test
X 
(Tier 4)
Blood for thyroid function 
tests k
X 
(Tier 4)
Urine drug screen
X 
(Tier 4)
X
X
Serum pregnancy test l
X 
(Tier 4)
Urine pregnancy test l
X
Safety brain MRI m
X 
(Tier 5)
Xm
DAT brain imaging, MIBG 
scan  n
X 
(Tier 6)
CSF sample by LP for PK 
and PD biomarkers o
X
X
Plasma sample for PK p
X
X
X
X
X
X
PGx sampleq
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Randomization c
X
Dispense study drug
X
X
X
X
X
CFI = Cognitive Fluctuation Inventory, CGIC-DLB = Clinician Global Impression of Change - in Dementia with Lewy Bodies, CIBIC-Plus = Clinician’s Interview Based 
Impression of Change Plus Caregiver Input, CIBIS-Plus = Clinician Interview Based Impression of Severity plus Caregiver Input, CSF = cerebrospinal fluid, C-SSRS = 
Columbia Suicide Severity Rating Scale, DAT = dopamine transporter, DEMQOL = Dementia Quality of Life, DLB = dementia with Lewy bodies, ECG = electrocardiogram, 
ED = early discontinuation, EQ-5D = EuroQol Five Dimensions Questionnaire, GDS = Geriatric Depression Scale, HYS = Hoehn and Yahr Scale, LP = lumbar puncture, 
MIBG = [(123)I]-metaiodobenzylguanidine, MMSE = Mini-Mental State Examination, MoCA = Montreal Cognitive Assessment, MRI = magnetic resonance imaging, NPI = 
Neuropsychiatric Inventory, PD = pharmacodynamic, PGx = pharmacogenomic, PK = pharmacokinetic, SCOPA-Sleep = Scales for Outcome in Parkinson’s disease-Sleep, 
SFQ = Short Fluctuation Questionnaire, UPDRS-III = Unified Parkinson’s Disease Rating Scale Part III.
a:  A window of ±3 days will be permitted for Visit 4 to 9 (Follow-Up) inclusive.


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b: The Screening Visit takes place over a period of up to 5 weeks. Subjects who complete screening assessments in less than 5 weeks may proceed to the Baseline Period.  At 
Screening, assessments are grouped into tiers and should be performed sequentially. Subjects will need to satisfy the eligibility criteria in each tier before proceeding to the next 
tier.  Subjects who cannot complete screening within 5 weeks should be discussed with the sponsor for extension of the Screening Period by up to 2 weeks.
c:  Visit 2 is the Baseline Visit and may be conducted up to 1 week before the first dose of study drug (ie, from Day -7 to Day -1). The Baseline Visit should be at least 2 weeks 
after the day of Screening Visit Tier 2 assessments. After completion of study assessments subjects who are eligible will be randomized to placebo or E2027.  They will be 
dispensed with study drug before leaving clinic at Visit 2. Visit 3 (Day 1) will be conducted by telephone. On Day 1 the subject will start taking study drug in the morning at 
home. The site study staff will telephone the subject/caregiver to check that the subject has taken study drug and to elicit any AEs.  Subjects who develop acute illnesses which 
make it inappropriate to start taking study drug may have their Baseline Period extended by 1 week after discussion with the sponsor medical monitor.
d:  Subjects who discontinue study drug prematurely for any reason will undergo an Early Discontinuation (ED) Visit within 7 days of their final dose of study drug.  In addition, 
subjects who prematurely discontinue study drug are expected to continue in the study for the originally scheduled visits, starting with next such visit that is >7 days after the 
ED Visit. Subjects who prematurely discontinue the study should attend at least 1 originally scheduled visit after the ED Visit. 
e:  Unscheduled visits may be conducted at any time as clinically indicated in the judgment of the investigator or as specified in the protocol.  Not all assessments indicated under 
Unscheduled Visits need to be conducted – actual assessments needed will be determined by the investigator or as specified in the protocol and will be based on the specific 
visit.
f:  At Screening, Tier 2 assessments in subjects should be performed in the following order:  MMSE and GDS first; then MoCA and SCOPA-Sleep.  The caregivers or informants 
should complete the SFQ, CFI and NPI. Subjects who do not meet eligibility criteria on MMSE or GDS should be screen failed and the other assessments do not need to be 
performed. The caregiver or informant must attend in person with the subject.  The above assessments should be completed before more invasive procedures (eg, physical 
examination, ECG, blood draws). Assessments at all other tiers are not required to be performed in any prespecified order.
g:  At Visits 2, 6, 8, ED Visit and FU Visit, study assessments should be conducted at approximately the same time of the day whenever possible (preferably in the morning).  The 
MoCA should be administered first. It is recommended that after the MoCA the following efficacy assessments in subjects should be performed in the following overall order 
(other study assessments may be conducted in between these efficacy assessments):  CIBIS/CIBIC-Plus, MMSE (Visit 8 only) and SCOPA-Sleep. The caregiver or informant 
will also complete the CIBIS/C-Plus, NPI and CFI.  The caregiver or informant must attend in person with the subject.  The CIBIS-Plus and CIBIC-Plus should be performed 
by an independent rater from other scales. As far as possible efficacy assessments should be completed before more invasive procedures (eg, physical examination, ECG, blood 
draws) unless otherwise specified. At Visits 6, 8 and ED Visit the MoCA should be the first clinical scale to be administered postdose and before the first postdose PK sample.  
At Visits 6, 8 and ED Visit the investigator should complete the CGIC-DLB after reviewing all the subject’s efficacy endpoints. 
h:  Single measurements of vital signs will be performed after subject has been resting supine for at least 10 minutes. Vital signs include temperature, respiratory rate, supine blood 
pressure and pulse. Blood pressure and pulse will be measured again after standing up for 2 min. At Week 2 (Visit 4), Week 6 (Visit 6) and Week 12 (Visit 8) (or ED Visit)
vital signs will be taken at 1 – 3 hours postdose, before PK sampling. At Week 9 (Visit 7) vital signs will be taken at 1 – 4 hours postdose, before PK sampling. (revised per 
Amendment 01)
i:  Triplicate ECG will be performed after subject has been resting supine for at least 10 min.  The mean QTcF and other ECG intervals will be determined.
j:  Clinical laboratory tests consist of hematology (complete blood count), clinical chemistry and urinalysis.  In subjects who participate in the CSF substudy, clotting screen (PT,
APTT, and INR) will also be performed only at the Screening Visit after eligibility has been established and consent for CSF has been given, but before the LP. 
k:  Thyroid function tests include thyroid stimulating hormone, free triidothyronine, and free thyroxine.
l:  Female subjects who are <60 years of age and not surgically sterilized.
m:  Safety MRI of the brain will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence 
images at screening.  MRI of the brain will be read by an approved central reader.  Safety MRI of the brain may be performed at Unscheduled Visits if deemed appropriate by 
the investigator, but is not required for all Unscheduled Visits.  Subjects who are rescreened do not need to have a new MRI at rescreening if there was an MRI within 90 days 
before rescreening that did not have exclusionary characteristics. 
n:  DAT brain imaging scan or myocardial MIBG scan will be performed by the local hospital radiology department in accordance with local procedures and must be performed at 
least 7 full days prior to Baseline. The rules regarding when DAT brain imaging or MIBG scan will be performed are specified in Inclusion Criterion 2. 


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o:  CSF will be collected by LP in subjects who participate in the CSF substudy.  During Screening CSF may be collected at any time after completion of screening procedures and 
a subject is deemed eligible at least 1 week before Visit 2; if necessary in these subjects the Screening Period may be extended by 1 week after discussion with the sponsor 
medical monitor.  CSF will be collected again at Visit 7. CSF will be collected in the morning at approximately the same time, either fasted (preferred) or at least 2 h after 
breakfast.  The timing of the Screening CSF collection needs to be scheduled carefully such that subsequent collection (at Visit 7) can be performed at a similar time of day 
(±2 hours) for each individual subject.  A gravity drip collection method must be used.  Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  If the LP and cognitive tests are performed on the same day, the LP must be performed after the cognitive tests are completed.  At Visit 7, a predose blood sample 
for PK will be taken first, followed by LP.  Subjects will then be dosed with study drug and a PK sample will be collected at 1 – 4 hours postdose. If Visit 7 occurs after an ED 
Visit, blood PK samples and CSF will not be collected.
p:  The day before the visits at which PK sampling will be done, the site study team will phone the subject and caregiver/informant to remind the subject not to take the study drug 
in the morning of the visit on the next day.  In the morning of the day of the visit, the subjects should take breakfast at home as normal if applicable.  Thereafter a predose PK 
sample will be taken in clinic. Study drug will be administered and 1 postdose PK sample will be taken:  1 - 3 hours postdose at Week 2 (Visit 4).  Study drug will be 
administered and 2 postdose PK samples will be taken:  1 - 3 hours postdose and 4 - 8 hours postdose at Week 6 (Visit 6) and Week 12 (Visit 8) (or ED Visit).  At Week 6 
(Visit 6) and Week 12 (Visit 8) (or ED Visit) study drug will be administered before efficacy assessments are performed.  Study drug will be administered and 1 postdose PK 
sample will be taken 1 - 4 hours postdose at Week 9 (Visit 7).  In subjects who participate in the CSF substudy a predose PK sample will be collected at Week 9 (Visit 7), 
followed by CSF collection. The subject will then be dosed with study drug and a PK sample will be collected at 1 - 4 h postdose.  In addition, subjects or their caregivers/ 
informants will need to record the time of dosing of study drug at home for 2 days before these visits.  If these visits take place after the ED Visit, blood PK samples will not be 
collected. 
q:  PGx participation is voluntary.  For subjects who have provided separate informed consent to participate in the PGx assessment, a blood sample for genomic DNA will be 
collected at the Baseline Visit.  If it cannot be collected at the designated time point, it may be collected at a time point after baseline.


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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 for the timings of the procedures and assessments to be performed 
during the study.  See Sections 9.1 and 9.5 for a full description of the procedures and 
assessments, respectively, to be performed during this study.
Table 7 presents the number of blood and CSF samples, and the estimated total volume of 
blood and CSF that will be collected throughout the study. Additional samples may be taken 
at the discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.  Actual specimen volumes may 
vary based on local regulations.  
Table 7
Summary of Estimated Blood and CSF Sample Volumes
Assessment
Total 
Number of 
Collection 
Time 
Points
Number of Time Points × Volume per 
Collection (mL)
Total 
Volume
(mL)
Screening
Visit
Baseline Visit
(predose)
Treatment 
and 
Follow-Up 
Periods
Blood
Chemistry
(revised per Amendment 01)
4
1 × 2.5
1 × 2.5
2 × 2.5
10.0
Vitamin B12
1
1 × 1.3
None
None
1.3
TSH, T4, T3, βHCG
1
1 × 2.5
None
None
2.5
Hematology
(revised per Amendment 01)
4
1 × 2.0
1 × 2.0
2 × 2.0
8.0
INR, prothrombin time, PTT
(revised per Amendment 01)
1
1 × 2.0
2.0
PK
10
None
None
10 × 6
60
PGx
1
--
1 × 6
None
6
Total blood volume to be collected
(revised per Amendment 01)
10.3
10.5
69
89.8
CSF
PK and PD
2
1 × 6
--
1 × 6
12
Total CSF volume to be collected
6
--
6
12
βHCG = beta-human chorionic gonadotropin, CSF = cerebrospinal fluid, INR = international normalized 
ratio, PGx = pharmacogenomics, PK = pharmacokinetic(s), PTT = partial thromboplastin time, TSH = 
thyroid stimulating hormone, T3 = triiodothyronine, T4 = thyroxine.
Note:  Actual volumes may be less, based on regional differences in Central Laboratories. 


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of LBD and 
other forms of dementia.
Further discussion of the selection of the efficacy endpoints is 
provided in Section 9.2.
Standard safety assessments incorporated into this protocol include assessment of AEs and 
SAEs, measurement of vital signs, clinical laboratory assessments, physical examinations, 
neurologic examinations, ECG measurements, assessments of suicidal thinking and behavior, 
and UPDRS-III. Safety MRI of the brain may be performed at Unscheduled Visits if deemed 
appropriate by the investigator. 
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
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 24 hours from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the last visit after the last 
dose of study drug.  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 or any 
protocol-required procedure should be reported to the sponsor regardless of the length of time 
that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
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.
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.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor, 
or its designee, to be filed in the sponsor’s Trial Master File.


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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any pregnancy in a female partner of 
a male subject in which the estimated date of conception is either before the last visit or within 
98 days of last study treatment (revised per Amendment 05), or any exposure to study drug 
through breastfeeding during study treatment or within 28 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 Events Associated with Special Situations
9.5.4.3.1
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 protocol
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.


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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the AE eCRF and also 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 AE eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, 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
AEs 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.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to the 
competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects (revised per Amendments 02 and 
05)
There are no safety signals identified in clinical studies conducted to date to warrant specific 
discontinuation criteria for individual subjects based on safety data. Most adverse events on 
E2027 were mild to moderate and there were no subjects who discontinued treatment due to 
adverse events. Therefore the investigator should exercise clinical judgement to decide if a 


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subject should be discontinued, except for specific situations described below. (revised per 
Amendment 02)
Skin Rash
As already described in Section 9.5.1.5.1, in subjects with skin rash, if it is concluded after 
dermatologist review that the skin rash is likely to be a drug rash due to study drug, then the 
study drug should be permanently discontinued if the rash has any of the following 
characteristics (revised per Amendment 02):

A bullous rash regardless of severity  (revised per Amendment 02)

A moderate to severe nonbullous rash  (revised per Amendment 02)
As already described in Section 9.5.1.5.1, in subjects with skin rash, if the rash is considered 
by the investigator to be related to study drug but has resolved before the dermatologist review 
then the study drug should be permanently discontinued if the rash has any of the following 
characteristics: 
•
A bullous rash regardless of severity (revised per Amendment 02)
•
A moderate to severe nonbullous rash (revised per Amendment 02)
Prolongation of QTcF Interval on ECG
Subjects who have mean QTcF on triplicate ECG >500 ms should be discontinued. (revised 
per Amendment 02)
Use of Prohibited Medications
As per Section 9.4.7.2, subjects who start treatment with any of these medications during the 
study will be discontinued due to the risk of PK or PD interactions (revised per Amendment 
02):

Drugs known to be strong inhibitors of cytochrome P450 (CYP) 3A, which increase 
exposure of drugs that are CYP3A substrates by >5 fold, grapefruit, grapefruit juice, and 
grapefruit products.  (revised per Amendment 02)

Drugs known to be moderate to strong inducers of CYP3A.  (revised per Amendment 02)

Drugs known to cause prolongation of the QT interval, including but not limited to drugs 
that may cause cardiac arrhythmias.  (revised per Amendment 02)

Drugs that are PDE inhibitors (eg, theophylline, aminophylline, sildenafil, tadalafil, 
vardenafil, dipyridamole, roflumilast, apremilast, inamrinone, milrinone, and enoximone)  
(revised per Amendment 02)
As per Section 9.4.7.2, subjects who start treatment with any of these medications during the 
study will be discontinued due to interference with efficacy assessments or safety (revised 
per Amendment 02):

Anticholinergic drugs that have CNS activity.  (revised per Amendment 02)


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
Pimavanserin.  (revised per Amendment03)

In subjects who participate in the CSF substudy only, if they start anticoagulants 
(eg, heparin, heparin derivatives, non-heparin derivatives, warfarin, dabigatran) or dual 
antiplatelet therapy (eg, aspirin and clopidogrel together) before their 2nd CSF collection 
at 9 weeks postrandomization, they will be discontinued from the CSF substudy.  (revised 
per Amendment 02)
Decline to Loss of Capacity to Consent

As per Section 5.3, in countries where local laws/regulations do not permit subjects 
lacking capacity to consent to participate in this study, then subjects who have declined to 
the point of lacking capacity to consent during the study will be discontinued. (revised 
per Amendment 02)
Contraception Requirement in Male Subjects
Male subjects who are in the treatment period and who meet the criteria that requires them and 
their female partners to practice contraception as specified in Section 9.4.7.3, but who cannot 
comply or are unwilling to do so, will be discontinued.  (revised per Amendment 05)
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  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 6).
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 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.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons:  AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more secondary reason(s) for discontinuation.  Study disposition information will be 
collected on the Subject Disposition eCRF.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
AEs associated with abuse or diversion will be appropriately reported as AEs and monitored 
per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.


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During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is planning 
to do so in the future.  When the subject is going to receive medical care by another physician, 
the investigator, with the consent of the subject, will inform the other physician that the subject 
is participating in the clinical study.
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 eCRFs 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 eCRF 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 eCRF.  The investigator or designee as identified on Form 
FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs 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 eCRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding and a snapshot of the 


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database is obtained and released for unblinding.  Statistical analyses will be performed using 
SAS software or other validated statistical software as required.  Details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data 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
9.7.1.1.1
PRIMARY ENDPOINTS

Change from baseline in the MoCA total score at 12 weeks of treatment

CIBIC-Plus scale at 12 weeks of treatment
9.7.1.1.2
SECONDARY ENDPOINTS
(Order of secondary endpoints revised per Amendment 05)

CGIC-DLB at 12 weeks of treatment

Change from baseline at 12 weeks of treatment in the following endpoints:  
◦
CFI score
◦
MMSE total score
◦
NPI total score, subscores and caregiver distress score

Safety and tolerability of E2027 as measured by (revised per Amendment 02):
◦
Incidence of adverse events including severe AEs, serious AEs, AEs resulting in 
discontinuation  (revised per Amendment 02)
◦
Incidence of orthostatic hypotension and orthostatic tachycardia  (revised per 
Amendment 02)
◦
Incidence of markedly abnormal laboratory values and shifts from baseline of 
laboratory values  (revised per Amendment 02)
◦
Incidence of abnormal ECG parameters and abnormal ECG findings  (revised per 
Amendment 02)
◦
Incidence of suicidality based on C-SSRS  (revised per Amendment 02)
◦
Changes from baseline in the total score of UPDRS-III (revised per 
Amendment 02)
9.7.1.1.3
EXPLORATORY ENDPOINTS 

Change from baseline at 12 weeks of treatment in the following endpoints:  
◦
SCOPA-Sleep total score and subscores

Change from baseline at 12 weeks of treatment in the following endpoints:


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◦
Each of the 5 domain scores of the DEMQOL and DEMQOL-Proxy
◦
EQ-5D utility score and EQ-5D health status rating

Percentage change from baseline in CSF cGMP concentration after 9 weeks of treatment
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postrandomization safety assessment

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose 
of study drug and have baseline and at least 1 postrandomization coprimary efficacy 
measurement

The Per Protocol Analysis Set (PPS) is the subset of subjects in the Full Analysis Set who 
sufficiently complied with the protocol. It may include subjects who complete certain pre-
specified minimal exposure to the treatment and have no major protocol violations such as 
wrong diagnosis, error in treatment assignment, use of inhibited medication and poor 
compliance. The precise reasons for excluding subjects from the PPS will be fully defined 
and documented before database lock.

The PK Analysis Set is the group of subjects with at least 1 quantifiable plasma E2027 
concentration with a documented dosing history

The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 
1 PD parameter

The PK/PD Analysis Set is a group of subjects with at least 1 quantifiable plasma E2027 
concentration, except for placebo subjects, and at least 1 PD measurement with a 
documented dosing history.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  
Study Completion:  the number (percent) of randomized and treated subjects who completed 
the study and who discontinued from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data reported 
on the Subject Disposition (Study Phase) eCRF.  The number (percent) will be presented by 
treatment group and total for all subjects. 
Completion of Study Treatment:  the number (percent) of randomized and treated subjects who 
completed study drug and who discontinued from study drug will be summarized according to 
the primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on Early Discontinuation from Study Drug eCRF.  The 
number (percent) will be presented by treatment group and total for all subjects.  Subjects who 


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discontinued study treatment but were followed up for efficacy assessments after treatment 
discontinuation will also be summarized.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE total score; categorical variables include sex, age 
group (equal or less than 65 years, age greater than 65 years), race, ethnicity, region, treatment 
with AChEIs (no or yes), and treatment with memantine (no or yes).  (revised per 
Amendment 03)
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and WHO 
DD preferred term (PT).  Prior medications will be defined as medications that stopped before 
the first dose of study drug.  Concomitant medications will be defined as medications that 
(1) started before the first dose of study drug and were continuing at the time of the first dose 
of study drug, or (2) started on or after the date of the first dose of study drug up to the date of 
the last dose.  All medications will be presented in subject data listings.
Medications taken within the 4-week Follow-Up Period will also be recorded.
9.7.1.6
Efficacy Analyses
The significance level for all efficacy endpoint analyses is 0.05 (2-sided), unless otherwise 
stated, with no adjustments for multiplicity.  The efficacy analyses will be performed on the 
FAS except per protocol analysis will be performed on the PPS.
Baseline for the primary and secondary efficacy endpoints is defined as the last pretreatment 
assessment.  An additional baseline, based on the mean of all prerandomization values at the 
Screening and Baseline assessment, will be explored due to assess potential prerandomization 
variability.  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
E2027 is planned for use as a symptomatic treatment in subjects with DLB.  The treatment 
effect of E2027 may be confounded by the use of rescue medications during the study. For the 
purposes of statistical analysis, rescue medications are defined as medications for treatment of 
symptoms of DLB that are prohibited or restricted (as specified in Section 9.4.7.2) and they 
are not used in accordance with the rules in Section 9.4.7.2. 
This confounding may mask the true treatment effect of E2027 in treating subjects with DLB. 
The treatment effect of interest will be the efficacy as measured by coprimary endpoints that 


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would be observed at 12 weeks without initiation or dose change of any prohibited or restricted
medications as mentioned above regardless of whether or when the assigned treatment was 
discontinued due to adverse event, lack of efficacy or any other events related to treatment or 
study outcome.  The target population (DLB subjects) is defined by inclusion/exclusion 
criteria. 
There are 2 coprimary efficacy endpoints, change from baseline in the MoCA total score at 
12 weeks and CIBIC-Plus scale at 12 weeks.  Overall, there are 2 null hypotheses (H0) to be 
tested in the primary analysis:  

H01:  There is no difference in the mean change from baseline in the MoCA total score at 
12 weeks between E2027 and placebo.

H02:  The proportional odds ratio based on CIBIC-Plus scale at 12 weeks between E2027 
and placebo is equal to 1.
The corresponding 2 alternative hypotheses are that there is a difference in the mean change 
from baseline in MoCA total score at 12 weeks in this coprimary endpoint between E2027 and 
placebo and the proportional odds ratio based on CIBIC-Plus scale at 12 weeks between E2027 
and placebo is not equal to 1.
The study will be considered positive if statistically significant improvement is observed in 
both coprimary endpoints in the E2027 treatment group. 
The change from baseline of MoCA total score for E2027 compared to placebo will be 
analysed using the approach proposed by Mehrotra, et al. (2017) with slight modification based 
on reasons for missing.  The following is a list of the missing reasons and their missing 
mechanisms:

Data not observed because of dropouts due to AEs, lack of efficacy or any other events 
related to treatment or study outcome will be considered as missing not at random
(MNAR).

The effect had rescue medication not been made available to subjects prior to Week 12 is 
not observable for subjects who initiated prohibited or restricted rescue medication. For 
these subjects, the data collected after initiation of prohibited rescue medication are 
assumed to contain no treatment effect in the E2027 treatment group. Technically, 
response data collected after initiation of prohibited rescue medication will be treated as 
MNAR such that response data as MNAR in the E2027 treatment group would be imputed 
by the mean response in the placebo treatment group as described by the imputation method 
below.

Data not observed because of dropouts due to intercurrent events definitely not related to 
treatment or outcome (eg, withdraw consent due to logistical problems) will be considered 
as missing at random (MAR). All events will be classified unambiguously in the statistical 
analysis plan.
The mean of missing endpoint values in the E2027 treatment group considered as MAR would 
be imputed using the mean of missing endpoint values of completers in the E2027 treatment 


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group and the mean of missing endpoint values in E2027 treatment group considered as MNAR 
will be imputed by the mean of the overall endpoint distribution under placebo based on the 
above missing reasons and the corresponding missing mechanisms.  The mean of the overall 
endpoint distribution under placebo will be obtained using mixed effects model of repeated 
measures (MMRM) within the placebo group assuming MAR. Test statistics and the P-value 
will be obtained as described by Mehrotra, et al. (2017).
The sensitivity analysis for MoCA will be a tipping point analysis based on control-based mean 
imputation proposed by Mehrotra, et al. (2017) in the same article, which is an increasingly 
more conservative means such that the P-value is equal to the pre-specified alpha 
(0.025 [1-sided]).  Drug benefit is interpreted as convincing if the tipping point is worse than 
the mean placebo dropouts.  Additional sensitivity analysis for different classification of 
missing mechanism (ie, all missing data will be considered as MNAR regardless of reason of 
dropouts), will be provided. 
In order to generate inputs for proposed primary and sensitivity analyses, a MMRM will be 
used for the E2027 group completers, placebo group completers, and all placebo group 
subjects.  The model will be adjusted for baseline MoCA, visit (Weeks 6 and 12), 
randomization stratification variable (receiving AChEI or not; geographical region [North 
America, Europe, Japan]), and baseline MoCA × visit as fixed effects.  An unstructured 
covariance matrix will be used to model the covariance of within subject effect.  The values of 
baseline MoCA will be adjusted using the overall baseline mean of all study subjects in 
computing LS-means.
The primary analysis of CIBIC-Plus scale at 12 weeks will be based on control-based pattern 
imputation at subject level (Yuan 2014).  The CIBIC-Plus scale at 12 weeks will be imputed 
as an ordinal response variable.  The same missing reasons and corresponding missing 
mechanism as in the analysis of change from baseline in MoCA total score will be used in this 
analysis.  Only the missing ordinal responses in E2027 treatment group considered as MNAR 
will be imputed by ordinal responses observed in the placebo group using a pattern-mixture 
model approach under MNAR assumption.  Other missing ordinal responses will be imputed 
assuming MAR. The CIBIC-Plus scale at 12 weeks (observed or imputed) will be analysed 
using proportional odds model, a special case of generalized linear mixed models (GLMM), in 
multiply imputed data sets.  The results obtained from all multiply imputed data sets will be 
combined for overall inference using Rubin's rules.  The GLMM model will include treatment, 
randomization stratification variables (receiving AChEI or not; geographical region [North 
America, Europe, Japan]) as fixed effects.  The model will be fitted using GLMM with a 
multinomial distribution and a cumulative logit link function. The proportional odds ratio 
estimate between E2027 and placebo, the corresponding 95% CI, and P-values will be 
presented.  
The sensitivity analysis for CIBIC-Plus scale will be a tipping point analysis based on multiple 
imputation at subject level using pattern mixture model approach (Yuan, 2014), which is based 
on an increasingly more conservative shift parameter (based on cumulative logit function 
values for CIBIC-Plus scale) such that the P-value is equal to the pre-specified alpha 
(0.05 [2-sided]).  Additional sensitivity analysis for different classification of missing 


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mechanism (ie, all missing data will be considered as MNAR regardless of reason of dropouts), 
will be provided.
If the proportional odds assumption is contradicted by the observed data in either entire 
population or any stratum, the GLMM method will be replaced by the non-parametric van 
Elteren test in both primary analysis and sensitivity analysis.  The CIBIC-Plus scale at 
12 weeks will be analysed using van Elteren test adjusting 2 randomization stratification 
variables (receiving AChEI or not; geographical region [North America, Europe, Japan]).  The 
null hypothesis corresponding to the van Elteren test is that there is no difference in the location 
of distribution of CIBIC-Plus scale at 12 weeks between E2027 and placebo.  The 
corresponding alternative hypothesis is that there is a difference in the location of distribution 
of CIBIC-Plus scale at 12 weeks between E2027 and placebo.
The potential effect of baseline MMSE on the primary result will be evaluated as an additional 
covariate in the primary model as appropriate.  Subgroup (eg, region, age group, baseline 
AChEI status, baseline MMSE group, and baseline memantine status) analyses will be 
performed as appropriate.  (revised per Amendment 03)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The CGIC-DLB scale will be analysed as ordinal response data in a manner similar to the 
primary analysis of coprimary endpoint based on CIBIC-Plus. Other secondary endpoints are 
continuous variables and will be analyzed in a manner similar to the primary analysis of 
coprimary endpoint based on MoCA.  
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
The sleep endpoint (SCOPA-Sleep total score and subscores) will be analyzed in a manner 
similar to the coprimary endpoint based on MoCA.  
If data permit, the relationship between E2027 PD effects on CSF cGMP (and other 
biomarkers) and various efficacy endpoints will be explored using correlation analysis and 
linear models will be fitted to further characterize the relationship between the changes in 
efficacy endpoints and the changes in E2027 PD variables as appropriate.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for plasma E2027 concentration listings and for summaries 
of CSF E2027 concentrations by day.  
A population PK approach will be used to characterize plasma E2027 PK.  For this approach, 
PK data from this study will be pooled with existing data from Phase 1 studies.  The effect of 
covariates on plasma E2027 PK, such as baseline characteristics/demographics, will be 
evaluated where feasible.  Derived plasma E2027 exposure parameters, such as steady state 
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will be calculated from the final PK model using the individual posterior estimates of the PK 
parameters and dosing history.  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of CSF PD biomarkers.  The 
percentage change from baseline in CSF cGMP and any other PD biomarkers after at least 
9 weeks of treatment with study drug postrandomization will be analyzed and presented 
graphically.
Pharmacodynamic/Pharmacokinetic Analyses
Data combining Phase 1 studies permitting, a population PK/PD approach will be used to 
characterize the relationship between plasma and/or CSF E2027 exposures and CSF PD 
biomarker levels.  For this approach, data from this study will be pooled with relevant data 
from Phase 1 studies.  The relationship between plasma and CSF E2027 exposure and the 
change from baseline of various efficacy endpoints will be explored graphically, as will the 
relationship between changes in CSF PD biomarkers and the change from baseline of various 
efficacy endpoints.  Any emergent relationships will be explored through population PK/PD 
modeling.
The PK and PK/PD analyses will be detailed in a separate analysis plan and the results will be 
provided in a stand-alone report.
Pharmacogenomic Analyses
Pharmacogenomic analyses may be performed and reported separately.  Details of these 
analyses, if appropriate, will be described in a separate analysis plan. 
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs, 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, and out-of-range 
vital signs, suicidality (C-SSRS), UPDRS-III, along with change from baseline in laboratory 
safety test variables, ECGs, and vital sign measurements (including orthostatic changes) will 
be summarized by treatment group.  
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure will be summarized by categories of cumulative weeks as well as by 
categories of duration of exposure.  The number and percentage of subjects for each exposure 
category will be presented by treatment group. Duration of exposure is the number of days 
between the date the subject received the first dose of study drug and the date the subject 
received the last dose of study drug and will be summarized using descriptive statistics for 
continuous variable by treatment group. Overall exposure (number of subject-weeks) is 


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defined as summation over all subjects’ exposure durations and will be summarized by 
treatment group. 
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 19.0 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 TEAE is defined as:

An AE that emerges on or after start of study treatment or within 28 days following the last 
dose of study drug, having been absent at pretreatment (Baseline) or

Reemerges on or after start of study treatment, having been present at pretreatment 
(Baseline) but stopped before treatment, or

Worsens in severity on or after start of study treatment relative to the pretreatment state, 
when the AE is continuous.  
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  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 an SOC and PT, even if the subject experienced 
more than 1 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.
The number (percentage) of subjects with treatment-related TEAEs, treatment-emergent 
serious adverse events (SAEs) and TEAEs leading to discontinuation from study drug will be 
also summarized by SOC and PT.  Subject data listing for each above type of AEs and AEs 
leading to death will also be provided. 
AEs will be summarized by the following subgroups:  region, treatment with AChEIs (no or 
yes), and treatment with memantine (no or yes).  (revised per Amendment 03)
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
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 


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baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
Appendix 2 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values (TEMAVs).  
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from 
baseline to a Grade of 2 or higher.  For phosphate, a TEMAV was defined as a postbaseline 
value with an increase from baseline to a Grade of 3 or higher.  When displaying the incidence 
of TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, respiratory 
rate, temperature, weight), and changes from baseline will be presented by visit and treatment 
group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and treatment group.  ECG interpretation (categorized as normal; abnormal, not clinically 
significant; and abnormal, clinically significant) will be presented by visit and treatment group 
using frequency count. The number (percentage) of subjects with post-baseline abnormal ECG 
result in QTcF will be summarized by treatment group. 
9.7.1.8.6
OTHER SAFETY ANALYSES
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS responses will be mapped to C-CASA (Columbia- classification algorithm of 
suicide assessment). The incidence of suicidal ideation or suicidal behavior will be summarized 
by treatment group. Continuous variables will be summarized by descriptive statistics; number 
of subjects, mean, standard deviation, median, minimum, and maximum and categorical 
variables by number (percentage) of subjects.
UPDRS-III (Unified Parkinson’s Disease Rating Scale Part III:  Motor Examination)
Changes from baseline in the total score of UPDRS-III will be summarized using descriptive 
statistics for continuous variable by visit and treatment group.
9.7.1.9
Other Analyses
The quality of life endpoints (DEMQOL and DEMQOL-Proxy domain scores, and the EQ-5D 
and EQ-5D Proxy scores) after 12 weeks of treatment and the percentage change from baseline 
in CSF cGMP concentrations after 9 weeks of treatment will be analysed using ANCOVA or 
rank-based ANCOVA as appropriate.  The ANCOVA model will include baseline as a 
covariate, with treatment group and randomization stratification variables as factors.


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9.7.2
Determination of Sample Size
The MoCA scale was assessed in DLB subjects and reported in Biundo et al. (2016).  The 
observed mean change from baseline in the MoCA total score at 1 year in this report 
is -1.04 points and the corresponding standard deviation (SD) is 1.32 points.  An estimation of 
the mean change from baseline in the MoCA total score at 3 months is 
approximately -0.26 points using linear interpolation.  It is assumed that E2027 would improve 
the MoCA total score as compared with baseline and achieve a mean treatment difference of 
approximately 0.6 points between E2027 and placebo at 12 weeks.  The SD of change from 
baseline in the MoCA total score at 3 months is expected to be smaller than that at 1 year.  A 
conservative estimate of the SD of change from baseline in the MoCA total score is 1.3 points 
at 12 weeks.  
In a 12-week donepezil monotherapy study in subjects with DLB (E2020-J081-431), the 
estimated proportional odds ratio based CIBIC-Plus scale for donepezil 10 mg relative to 
placebo was 6.14.  It is assumed that E2027 would achieve a proportional odds ratio of 2.607 
relative to placebo (ie, 42% of the effect size observed in the above donepezil study).  
With 80 subjects completing per arm (for 91 randomized subjects per arm, assuming a 12% 
dropout rate), this study will have approximately 80% power to detect the above effect sizes 
(ie, mean treatment difference of approximately 0.6 points based MoCA total score and 
proportional odds ratio of 2.607 based on CIBIC-Plus scale for E2027 relative to placebo) in 
both coprimary endpoints simultaneously.  Therefore, the total sample size of 182 randomized 
subjects is planned, assuming a 12% dropouts rate.
Participation in the CSF substudy is voluntary. It is estimated that approximately 30% of 
subjects will participate in the CSF substudy. If the dropout rate in the CSF substudy is 12%, 
20%, or 50%, then the number of subjects having final CSF assessment would be 
approximately 48, 44, or 27, respectively. The estimated standard deviation of percent change 
from baseline of cGMP concentrations after 9 weeks of treatment from pooled subjects in the 
CSF substudy is approximately 130%. The width of the 95% CI of treatment between E2027 
and placebo for the 3 different sample sizes above would be approximately 74%, 77%, or 96%, 
respectively. Since mean percent change from baseline of cGMP concentrations after 9 weeks 
of treatment in the E2027 and placebo groups are expected to be approximately 200% and 5%, 
respectively, the sample size of the CSF substudy would be adequate to detect the mean 
difference of percent change from baseline in cGMP concentrations after 9 weeks of treatment 
between the E2027 and placebo groups.
9.7.3
Interim Analysis
This is a fixed design.  There is no interim analysis of efficacy and no alpha spending before 
final analysis.  (revised per Amendment 03) 
An independent DSMB will convene at regular intervals to monitor the overall safety of the 
study and to make recommendations to the sponsor related to study safety as appropriate.  The 
DSMB will be asked to review the cumulative safety data up to the date identified to make a 
determination if the study is safe to proceed unchanged or to provide recommendations to the 


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sponsor as to how to proceed.  The study will proceed, including randomization of additional 
subjects, during DSMB safety reviews.  Details will be provided in the DSMB Charter.
9.7.4
Other Statistical/Analytical Issues
Not applicable. 
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision 
will be documented and described in the clinical study report.


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10 REFERENCE LIST
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Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-Larsen T, Larsen JP.  Performance on 
the dementia rating scale in Parkinson’s disease with dementia and dementia with Lewy 
bodies:  comparison with progressive supranuclear palsy and Alzheimer’s disease.  J Neurol 
Neurosurg Psychiatry. 2003;74:1215-1220.
Biundo R, Wies L, Bostantjopoulou S, Stefanova E, Falup-Percurariu C, Kramberger MG, 
Geurtsen GJ, Antonini A, Weintraub D, Aarsland D.  MMSE and MoCA in Parkinson’s disease 
and dementia with Lewy bodies:  a multicenter 1-year follow-up study.  J Neural Transm.
2016;123:431-438.
Boddy F, Rowan EN, Lett D, O’Brien JT, McKeith IG, Burn DJ.  Subjectively reported sleep 
quality and excessive daytime somnolence in Parkinson’s disease with and without dementia, 
dementia with Lewy Bodies and Alzheimer’s disease.  Int J Geriatr Psychiatry. 2007;22:  529–
535.
Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, et al.  Effects of rivastigmine 
in patients with and without visual hallucinations in dementia associated with Parkinson’s 
disease.  Movement Disorders. 2006;21(11):1899–1907
Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al.  Pimavanserin 
for patients with Parkinson’s disease psychosis:  a randomised, placebo-controlled phase 3 
trial.  Lancet. 2014;383:533–40.  
Domek-Łopacińska K, Strosznajder JB. Cyclic GMP metabolism and its role in brain 
physiology. J Physiol Pharmacol. 2005 Mar;56 Suppl 2:15-34.
Donaghy P, Thomas AJ, O'Brien JT.  Amyloid PET Imaging in Lewy body disorders.  Am J 
Geriatr Psychiatry. 2015;23(1):23-37.
Dubois B, Tolosa E, Katzenschlager R, Emre M, Lees AJ, Schumann G, et al.  Donepezil in 
Parkinson’s disease dementia:  a randomized, double-blind efficacy and safety study.  
Movement Disorders. 2012;27(10):1230-1238.
Grove RA, Harrington CM, Mahler A, Beresford I, Maruff P, Lowy, MT et al.  A Randomized, 
Double-Blind, Placebo-Controlled, 16-Week Study of the H3 Receptor Antagonist, 
GSK239512 as a Monotherapy in Subjects with Mild-to-Moderate Alzheimer’s Disease.  
Current Alzheimer Research. 2014; 11, 47-58.
Ikeda M, Mori E, Matsuo K, Nakagawa M, Kosaka K.  Donepezil for dementia with Lewy 
bodies:  a randomized, placebo-controlled, confirmatory phase III trial.  Alzheimer's Research 
& Therapy. 2015;7:4.  


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Li Z, Yu Z, Zhang J, Wang J, Sun C, Wang P, Zhang J.  Impact of rivastigmine on cognitive 
dysfunction and falling in Parkinson’s disease patients.  Eur Neurol. 2015;74:86-91.
Matsunaga S, Kishi T, Yasue I, Iwata N.  Cholinesterase Inhibitors for Lewy Body Disorders:  
A Meta-Analysis.  International Journal of Neuropsychopharmacology. 2015;1–15.
McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, et al.  Efficacy of rivastigmine 
in dementia with Lewy bodies:  a randomised, double-blind, placebo-controlled international 
study Lancet. 2000;356:2031–36.  
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al.  Diagnosis 
and management of dementia with Lewy bodies:  Fourth consensus report of the DLB 
Consortium.  Neurology. 2017;89:88-100
Mehrotra DV, Liu F, and Permutt T.  Missing Data in Clinical Trials: Control-Based Mean 
Imputation and Sensitivity Analysis.  Pharmaceutical Statistics. 2017; 16(5):378–92
Mori E, Ikeda M, MD, Kosaka K.  Donepezil for dementia with Lewy bodies:  a randomized, 
placebo-controlled trial.  Ann Neurol. 2012;72:41–52.
National Institute for Health and Care Excellence (NICE).  NICE guideline [NG97].  
Dementia: Assessment, Management and Support for People Living with Dementia and Their 
Carers. June 2018.  Available from: https://www.nice.org.uk/guidance/ng97
Noe E, Marder K, Bell KL, Jacobs DM, Manly JJ, Stern Y. Comparison of dementia with 
Lewy bodies to Alzheimer’s disease and Parkinson’s disease with dementia.  Movement 
Disorders. 2004; 19(1):60-7.
U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research.  Guidance for Industry.  Assessment of Abuse Potential of 
Drugs.  January 2017.
Walker Z, Possin KL, Boeve BF, Aarsland D.  Lewy body dementias.  Lancet. 2015;386,1683-
1697.
Yuan Y.  Sensitivity Analysis in Multiple Imputation for Missing Data.  SAS Global Forum 
2014 Proceedings.  Paper SAS270-2014.


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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 (or, if regionally required, the head of the medical institution) 
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).
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  (or if regionally 
required, the head of the medical institution) will allow the CRA to inspect the clinical, 
laboratory, and pharmacy facilities to assure compliance with GCP and local regulatory 
requirements.  The eCRFs 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 to 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


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
Copies or transcribed health care provider notes that have been certified for accuracy after 
production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging reports 
(eg, 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 (eg, 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

eCRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source

Electronic Clinical Outcome Assessment (e-COA) by self-reported measures
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except when 
a section of the eCRF itself is used as the source document.  Any correction to entries made on 
the eCRF 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.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
Efficacy and safety assessments are evaluated based on the data entered into e-COA.  The 
applicable data are input directly by each subject from the viewpoint of his/her health condition 
without the interpretation of the investigator.  
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
For the following items, the data recorded directly on the CRF are to be considered source 
data:  

reasons for discontinuation of study treatment


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
comments and other information on AEs [eg, severity, relationship to study drug, outcome

reasons for dose modification

indication for prior/concomitant medication

sampling times for drug concentrations

sampling times for clinical laboratory tests
The data collected by e-COA are also considered source data.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the investigator
(or if regionally required, the head of the medical institution or the designated representative)
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 (eg, 
Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 3 years have elapsed since the formal discontinuation 
of clinical development of the investigational product.
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 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 drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, 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 


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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 designated contractor) 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 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 


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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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12 APPENDICES


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Appendix 1
Diagnostic Criteria for Probable Dementia With Lewy 
Bodies (DLB) 
The diagnostic criteria for probable dementia with Lewy bodies (DLB) require:

Progressive cognitive decline of sufficient magnitude to interfere with normal social or 
occupational functions or with usual daily activities. 

Prominent or persistent memory impairment may not necessarily occur in the early stages 
but is usually evident with progress.

Deficits on tests of attention, executive function and visuospatial ability may be prominent 
and occur early.

At least 2 core clinical features, or 1 core clinical feature and at least 1 indicative biomarker.
The core clinical features are:  

Fluctuating cognition with pronounced variations in attention and alertness.

Recurrent visual hallucinations that are typically well formed and detailed.

REM sleep behavior disorder which may precede cognitive decline.

One or more spontaneous cardinal features of Parkinsonism:  these are bradykinesia 
(defined as slowness of movement and decrement in amplitude or speed), rest tremor or 
rigidity. 
In this study, patients with Parkinson disease dementia (PDD), which is dementia that occurs 
in the context of well-established Parkinson disease, are not eligible.  Therefore, the onset of 
dementia should not be greater than 1 year after onset of Parkinsonism.  The investigator should 
determine the time of onset of Parkinsonian motor features based on clinical evaluation.
For assessment for cognitive function, the investigator should take into account scores of the 
Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) used 
at screening.
In evaluation of the core clinical features, the investigator should take into account the scores 
in the Short Fluctuation Questionnaire (SFQ), Cognitive Fluctuation Inventory (CFI), 
Neuropsychiatric Inventory (NPI) and Unified Parkinson’s Disease Rating Scale Part III:  
Motor Examination (UPDRS-III) for cognitive fluctuation, hallucinations and parkinsonian 
motor features respectively.
Indicative biomarkers include:

Reduced dopamine transporter uptake in the basal ganglia on dopamine transporter (DAT)
brain scan

Abnormal (low uptake) in metaiodobenzylguanidine (MIBG) cardiac scan

Polysomnography (PSG) confirmation of rapid eye movement (REM) sleep without atonia


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When Parkinsonism is the only core feature of DLB in a patient with dementia, reduced DAT 
uptake warrants a probable DLB diagnosis provided that other disorders associated with 
cognitive impairment and reduced DAT uptake can be excluded.  
Clinicians should carefully interpret MIBG results in the light of possible confounding causes, 
including ischemic heart disease, heart failure, diabetes mellitus, peripheral neuropathies, and 
medications that may cause reduced uptake including labetalol, reserpine, tricyclic 
antidepressants, and over-the-counter sympathomimetics.


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Appendix 2
Sponsor’s Grading for Laboratory Values
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109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0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ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0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
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ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0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


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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 
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).


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Appendix 3
Examples of Adverse Events That May Signal Drug Abuse Potential
Examples of Adverse Events That May Signal Drug Abuse Potential
Categories
Examplesa
Euphoria-related terms
1
Euphoric mood
Euphoric mood
Feeling high
Euphoria
Felt high
Euphoric
High
Exaggerated well-being
High feeling
Excitement excessive
Laughter
2
Elevated mood
Elevated mood
Elation
Mood elevated 
3
Feeling abnormal
Feeling abnormal
Funny episode
Cotton wool in head
Fuzzy
Feeling dazed
Fuzzy head
Feeling floating
Muzzy head
Feeling strange
Spaced out
Feeling weightless
Unstable feeling
Felt like a zombie
Weird feeling
Floating feeling
Spacey
Foggy feeling in head
4
Feeling drunk
Feeling drunk
Intoxicated
Drunkenness feeling of
Stoned
Drunk-like effect   
Drugged
5
Feeling of relaxation
Feeling of relaxation
Relaxed
Feeling relaxed
Increased well-being
Relaxation
Excessive happiness
6
Dizziness
Dizziness
7
Thinking abnormal
Thinking abnormal
Thinking disturbance
Abnormal thinking
Thought blocking


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Examples of Adverse Events That May Signal Drug Abuse Potential
Categories
Examplesa
Thinking irrational   
Wandering thoughts
8
Hallucination
Hallucination
Floating
Illusions
Rush
Flashbacks
Feeling addicted
9
Inappropriate affect
Elation inappropriate
Inappropriate elation
Exhilaration inappropriate
Inappropriate laughter
Feeling happy inappropriately
Inappropriate mood elevation
Inappropriate affect   
Terms indicative of impaired attention, 
cognition, and mood 
10
Somnolence
Somnolence
11
Mood disorders and 
disturbances
Mental disturbance
Mood swings
Depersonalisation
Emotional lability 
Psychomotor stimulation
Emotional disorder
Mood disorders
Emotional distress
Emotional and mood disturbances
Personality disorder
Delirium
Impatience
Delirious
Abnormal behavior
Mood altered
Delusional disorder
Mood alterations
Mood instability
Irritability
Dissociative/psychotic terms
12
Psychosis
Psychosis 
Psychotic episode or disorder
13
Aggression
Aggression
14
Confusion and 
disorientation
Confusion and disorientation
15
Dissociative State
Dissociation
Detached
Disconnected
Sensation of distance from one's 
environment
Derealisation
Loss of a sense of personal identity


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Examples of Adverse Events That May Signal Drug Abuse Potential
Categories
Examplesa
Depersonalisation   
Related terms not captured elsewhere
16
Drug tolerance
Drug tolerance  
17
Habituation
Habituation
18
Substance related 
disorders
Substance-related disorders
Physical dependence or withdrawalb
19
Drug withdrawal 
syndrome
Drug withdrawal syndrome
Chills
Headache
Decreased concentration
Anxiety
Agitation
Nausea
Irritability
Vomiting
Sleep disturbances
Tremor
Mood changes
a:  Examples include terminology provided in the following guidance:  U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research.  Guidance for Industry.  Assessment of Abuse Potential of Drugs.  January 2017.  The same term may apply to more than 
1 category.  A more comprehensive list of terms is provided in the eCRF Completion Guidelines.  
b:  Only for events observed within the first 4 weeks of last dose of study drug.


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Appendix 4
Cerebrospinal Fluid (CSF) Substudy (revised per 
Amendment 02)
This appendix describes the CSF substudy and consolidates the procedures for subjects who 
participate in the CSF substudy as already described in various sections of the main protocol.
Rationale
In the MAD Study 002, it was found that healthy subjects treated with E2027 at 50 mg QD for 
6 weeks achieved CSF cGMP increase from baseline by ~220% and this was sustained from 2 
weeks to 6 weeks. Internal data in Eisai suggested in subjects with DLB, there was ~17% 
reduction in CSF cGMP compared to healthy elderly subjects. Thus E2027 may increase 
neuronal cGMP in DLB subjects and improve cognition, but there may be differences in the 
PD response in DLB subjects compared to healthy subjects. Therefore this CSF substudy is 
undertaken to determine if E2027 achieves comparable CSF cGMP elevation as in healthy 
subjects, and will help to interpret any efficacy results on various cognitive or non-cognitive 
endpoints.
Exploratory Objectives
The CSF substudy aims to evaluate the effects of E2027 on CSF cGMP in subjects with DLB. 
The exploratory objectives are as described in Section 8.3:

To explore the PK/PD relationship between the exposure of E2027 in CSF/plasma and its 
effects on CSF PD biomarker endpoints, including CSF cGMP, if data permit

To explore the relationship between the E2027 PD effects (including CSF cGMP) with 
E2027 effects on various efficacy endpoints, if data permit
Eligibility Criteria
Inclusion Criteria:

Subjects must meet all the inclusion criteria in Section 9.3.1.

Provide separate informed consent for participation in the CSF substudy. If a subject 
lacks capacity to consent in the investigator's opinion, the subject's assent should be 
obtained, as required in accordance with local laws, regulations and customs, plus the 
written informed consent of a legal representative should be obtained (capacity to consent 
and definition of legal representative should be determined in accordance with applicable 
local laws and regulations).
Exclusion Criteria:

All the exclusion criteria in Section 9.3.2 apply.

Exclusion criterion 27 in Section 9.3.2 applies specifically to subjects participating in the 
CSF substudy, namely:


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◦
A bleeding disorder that is not under adequate control (including a plate count 
<50,000, international normalized ratio [INR] >1.5 or partial thromboplastin time 
[PTT] > upper limit of normal [ULN]).
◦
Any contraindications to lumbar puncture (LP) (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, or obesity to the 
extent that it makes LP technically difficult).
Substudy Design
Participation in the CSF substudy is voluntary. Subjects who do not wish to participate in the 
CSF substudy may still participate in the main study without CSF collection. CSF will be 
collected by lumbar puncture (gravity drip method) during Screening and again during the 
Randomization Phase after 9 weeks of treatment on study drug.
Subjects who participate in the CSF substudy will undertake screening as described in 
Section 9.1.1.  They will need to provide separate informed consent during screening before 
they can participate in the CSF substudy. Their informed consent for the CSF substudy should 
be provided at least 7 days before the Baseline Visit.  After they have completed all screening 
assessments and are considered eligible for the study, they will have a blood test for clotting 
screen (PT, APTT, and INR) performed before the lumbar puncture (Table 6). If their clotting 
screen is satisfactory, then a baseline CSF sample will be collected at least 7 days before the 
Baseline Visit.  If necessary, in these subjects the Screening Period may be extended by 1 week 
after discussion with the sponsor medical monitor.  
Subjects in the CSF substudy then proceed to the Baseline Period (Section 9.1.2), followed by 
the Treatment Period (Section 9.1.3). After they have completed 9 weeks of treatment, they 
will have a 2nd CSF sample collected at Visit 7.  The CSF samples will be collected in the 
morning at approximately the same time, either in the fasted state (preferred) or at least 2 hours 
after breakfast. The timing of the baseline CSF collection during screening needs to be 
scheduled carefully such that subsequent collection (at Visit 7) can be performed at a similar 
time of day (±2 hours) for each individual subject.  Subjects will be encouraged to stay at the 
site after completion of LP for medical observation.  If the LP and cognitive tests are performed 
on the same day, the LP must be performed after the cognitive tests are completed.
At Visit 7, a predose blood sample for PK will be taken first, followed by LP.  Subjects will 
then be dosed with study drug and a PK sample will be collected at 1 – 4 hours postdose.  If 
Visit 7 occurs after an ED Visit, blood PK samples and CSF will not be collected.
After completion of the Treatment Period, subjects will proceed to the Follow-Up Period 
(Section 9.1.4).
The study procedures for subjects who take part in the CSF substudy are already described in 
Table 6.


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As data permit, CSF cGMP will be assayed to evaluate the PD effects of E2027 in these 
subjects with DLB.  Other CSF PD biomarkers related to DLB or E2027 PD effects may also 
be assayed if appropriate.  CSF E2027 concentrations will also be determined.
Prohibited and Restricted Concomitant Drugs
Prohibited or restricted concomitant drugs are described in Section 9.4.7.2. Specifically for 
subjects in the CSF substudy:

Anticoagulants (eg, heparin, heparin derivatives, non-heparin derivatives, warfarin, 
dabigatran) and dual antiplatelet therapy (eg, aspirin and clopidogrel together) are 
prohibited from Screening Visit until after the 2nd CSF collection at 9 weeks 
postrandomization.  These subjects who start anticoagulants or dual antiplatelet therapy at 
any time before CSF collection at 9 weeks postrandomization will not participate in the 
CSF substudy.
Risks of CSF Substudy
The local anesthetic may cause burning sensation, a local skin rash or irritation. The lumbar 
puncture may result in local pain / discomfort during the procedure. 
The most common adverse effects from the lumbar puncture are headache and backache, 
caused by spinal fluid leaking from the puncture site. Approximately 10% of participants 
experience a headache and if a headache does occur, it usually improves while lying supine. 
The headache often resolves within 2 days, but in less than 5% of participants it can last longer. 
In subjects who have persistent, severe headache, injection of a blood patch may be required 
to stop the CSF leak.  
Other possible known side effects of a lumbar puncture are listed below:

Nausea

Vomiting

Dizziness

Back pain or discomfort

Infection

Bleeding, bruising or leakage of spinal fluid from the puncture site

Difficulty urinating

Allergic reaction to local anesthetic

Irritation to nerves with temporary numbness
Rare or very uncommon effects of lumbar puncture include low blood pressure, bleeding into 
the spinal canal, nerve damage or meningitis. These rare complications may be serious and 
could require hospitalization for urgent treatment, which may include antibiotics or surgery.  


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Statistical Analysis
Analysis of the primary efficacy endpoints, secondary efficacy endpoints, exploratory efficacy 
endpoints  and safety endpoints in subjects in the CSF substudy will be conducted together 
with subjects who are not in the CSF substudy, as specified in Section 9.7.1.6 and Section 
9.7.1.8. 
As per Section 9.7.1.6.3, in subjects in the CSF substudy, if data permit, the relationship 
between E2027 PD effects on CSF cGMP (and other biomarkers) and various efficacy 
endpoints will be explored using correlation analysis and linear models will be fitted to further 
characterize the relationship between the changes in efficacy endpoints and the changes in 
E2027 PD variables as appropriate.
As per Section 9.7.1.7.2, data combining Phase 1 studies permitting, a population PK/PD 
approach will be used to characterize the relationship between plasma and/or CSF E2027 
exposures and CSF PD biomarker levels.  For this approach, data from this study will be pooled 
with relevant data from Phase 1 studies.  The relationship between plasma and CSF E2027 
exposure and the change from baseline of various efficacy endpoints will be explored 
graphically, as will the relationship between changes in CSF PD biomarkers and the change 
from baseline of various efficacy endpoints.  Any emergent relationships will be explored 
through population PK/PD modeling.
The PK and PK/PD analyses will be detailed in a separate analysis plan and the results will be 
provided in a stand-alone report.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2027-G000-201
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Study To Evaluate the Efficacy, Safety and 
Tolerability of E2027 in Subjects With Dementia With Lewy 
Bodies
Investigational Product 
Name:
E2027
IND Number:
123614
EudraCT Number:
2017-003728-64
SIGNATURES
Authors:
 Neurology Business Group
Eisai Ltd.  
Date
 Neurology Business Group
Eisai Inc.
Date
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2027-G000-201
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Study To Evaluate the Efficacy, Safety and 
Tolerability of E2027 in Subjects With Dementia With Lewy 
Bodies
Investigational Product
Name:
E2027
IND Number:
123614
EudraCT Number:
2017-003728-64
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for 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

SAP_003.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2027-G000-201
Study Protocol 
Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, 
Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in 
Subjects With Dementia With Lewy Bodies
Date:
V4.0, 14 April 2020


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SIGNATURE PAGE
Author:
 
Neurology Business Group
[electronic signature in eDMS] 
Signature
Date:  ______________
Approval
Biostatistics:
Neurology Business Group
[electronic signature in eDMS]
Signature
Date: ________________
Study Director:
Neurology Business Group
[electronic signature in eDMS]
Signature
Date: ________________
PPD
PPD
PPD
PPD
PPD


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................3
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................8
3
INTRODUCTION.......................................................................................................11
3.1
Study Objectives ................................................................................................11
3.1.1
Primary Objectives ...................................................................................11
3.1.2
Secondary Objectives ...............................................................................11
3.1.3
Exploratory Objectives .............................................................................11
3.2
Overall Study Design and Plan...........................................................................12
4
DETERMINATION OF SAMPLE SIZE .....................................................................14
5
STATISTICAL METHODS ........................................................................................15
5.1
Study Endpoints.................................................................................................15
5.1.1
Primary Endpoints....................................................................................15
5.1.2
Secondary Endpoints................................................................................15
5.1.3
Exploratory Endpoint(s) ...........................................................................16
5.2
Study Subjects ...................................................................................................16
5.2.1
Definitions of Analysis Sets......................................................................16
5.2.2
Subject Disposition...................................................................................17
5.2.3
Protocol Deviations ..................................................................................17
5.2.4
Demographic and Other Baseline Characteristics......................................18
5.2.5
Prior and Concomitant Therapy................................................................19
5.2.6
Treatment Compliance..............................................................................19
5.3
Data Analysis General Considerations................................................................19
5.3.1
Pooling of Centers....................................................................................19
5.3.2
Adjustments for Covariates of Interest......................................................19
5.3.3
Multiple Comparisons/Multiplicity...........................................................20
5.3.4
Examination of Subgroups........................................................................20
5.3.5
Handling of Missing Data, Drop-outs, and Outliers ..................................21
5.3.6
Other Considerations ................................................................................21
5.4
Efficacy Analyses ..............................................................................................21
5.4.1
Primary Efficacy Analyses .......................................................................21
5.4.2
Secondary Efficacy Analyses....................................................................27
5.4.3
Exploratory Efficacy Analyses .................................................................29
5.5
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic 
Analyses ............................................................................................................30
5.6
Safety Analyses..................................................................................................30


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5.6.1
Extent of Exposure ...................................................................................30
5.6.2
Adverse Events.........................................................................................31
5.6.3
Laboratory Values ....................................................................................32
5.6.4
Vital Signs................................................................................................33
5.6.5
Electrocardiograms...................................................................................34
5.6.6
Other Safety Analyses ..............................................................................35
5.6.6.1
C-SSRS ..........................................................................................35
5.6.6.2
UPDRS-III......................................................................................35
5.7
Other Analyses...................................................................................................36
5.8
Exploratory Analyses.........................................................................................37
6
INTERIM ANALYSES...............................................................................................37
7
CHANGES IN THE PLANNED ANALYSES.............................................................37
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................38
8.1
Efficacy data handling........................................................................................38
8.1.1
Pre-randomization/Baseline Efficacy........................................................38
8.1.2
Treatment Duration for Efficacy Analyses................................................38
8.1.3
Efficacy Data Collected After the ED Visit...............................................39
8.1.4
Censoring of Efficacy Data Based on Changes in Medications .................39
8.2
Safety data handling...........................................................................................40
8.2.1
Baseline Safety.........................................................................................40
8.2.2
Treatment Duration for Safety Analyses ...................................................40
8.2.3
Handling of Replicate Data.......................................................................41
8.2.4
Safety Data Collected After the ED Visit..................................................42
8.3
Algorithms for Efficacy Parameters ...................................................................42
8.4
Algorithms for Safety Parameters.......................................................................44
9
PROGRAMMING SPECIFICATIONS .......................................................................46
10
STATISTICAL SOFTWARE......................................................................................46
11
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ...............................................46
12
REFERENCES............................................................................................................46
13
APPENDICES.............................................................................................................47
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results.....47
13.2
SPSS Syntax Files for DEMQOL and DEMQOL-Proxy.....................................51
13.3
EQ-5D-5L_Crosswalk_Index_Value_Calculator and SAS Syntax File for EQ-
5D......................................................................................................................61
13.4
Imputation of Missing Start and End Dates for AE and Concomitant 
Medication.........................................................................................................62


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Table 1
Summary of Changes (Version 4)
Changes in Version 4
Rationale
Section 5.4 Efficacy Analyses and Section 7 
Changes to Planned Analyses 
Revised the primary and secondary analyses o 
utilize MMRM for the primary analysis for 
non-EMA registration and have separate 
analyses for EMA registration.
These changes have been made due to 
correspondence with the FDA, separate 
analyses will be performed for the different 
registrations for the non-EMA and EMA.  
The supplementary analyses have been 
reduced to allow for clearer interpretation of 
the co-primary analyses.
Table 2
Summary of Changes (Version 3)
Changes in Version 3
Rationale
Sections 3.1.2, 5.1.2 and 5.4.2. Revised the 
order of the secondary efficacy objectives, 
endpoints and analyses.
To enable the secondary endpoints to be part 
of the statistical hierarchy of testing 
Section 5.2.3 Protocol Deviations. Removed 
restricted medications criteria.  Added criteria 
relating to exclusion criteria 6.
Due to blinded data review, it was found the 
assumption that the restricted medications 
would improve efficacy were incorrect, this 
is investigated in sensitivity analyses only.
As per Exclusion Criteria 6, Geriatric 
Depression Scale (GDS) greater than 8, may 
affect efficacy.
Section 5.4.1 Primary Efficacy Analysis.
Co-primary Analysis of Change from Baseline 
in the MoCA Total Score at 12 Weeks.  
Further define MAR and MNAR for the 
MoCA analysis.
For clarification purposes.
Section 5.4.1 Primary Efficacy Analysis, 
Section 5.4.2 Secondary Efficacy Analysis, 
Section 5.4.3 Exploratory Efficacy Analysis.  
Changes to censoring on restricted 
medications, removed from all and add as a 
sensitivity analysis on co-primaries only.
Due to blinded data review, it was found the 
assumption that the restricted medications 
would improve efficacy were incorrect, 
therefore the censoring of this data is moved 
to sensitivity analyses only.


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Table 3
Summary of Changes (Version 2)
Changes in Version 2
Rationale
Throughout the document: Editorial 
corrections are made to correct typos
For clarification purposes.
Throughout the document: based on Protocol 
Version 4, the addition of memantine
Added subgroup analyses for memantine 
use.
Section 4 “Sample Size” additional 
information on current sample size and study 
data
The clinical meaningful treatment 
difference and SD for MoCA total score 
assumptions have been updated based on 
partial blinded study data.
Section 5.2.2 “Subject Disposition”
Wording added to summarize overall and 
by stratification factors.
Section 5.2.4 “Demographic and Other 
Baseline Characteristics”
Added further variables to be summarized.
Section 5.4.1 “Co-primary Analysis of the 
CIBIC-Plus Scale at 12 Weeks”. Edited 
regarding censoring of AChEI and non-
AChEI restricted medications
“Table 4: Primary Efficacy Analyses” added.
Co-primary Analysis of the CIBIC-Plus 
Scale at 12 Weeks edited to add that 
changes in both AChEI and non-AChEI 
restricted medications will be censored.  
This is due to what CIBIC-Plus measures 
and maybe affected by changes in any of 
these medications.
Table added to describe all of the primary, 
sensitivity and supplementary analyses.
Section 5.4.2 and 5.4.3 “Secondary and 
Exploratory Efficacy Analyses”
“Table 5: Secondary Efficacy Analyses” 
added.
Clarification and additional analyses added 
regarding the censoring of changes in 
AChEI medications and censoring of both 
AChEI and non-AChEI restricted 
medications.
Table added to describe all the secondary 
analyses.
Section 5.6.5 “Electrocardiograms”
Further abnormal ECGs summary added.
Section 5.6.6.2 “UPDRS-III”
Added summary censoring data after 
changes in DLB medication.
Section 5.7 “Other Analyses”
Detail added for censoring of data based on 
medication changes.


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Table 3
Summary of Changes (Version 2)
Changes in Version 2
Rationale
Section 6 “Interim Analysis”, deleted.
Removed to coincide with decision to not 
do the adhoc futility analysis as per 
protocol amendment 03.
Section 8.1.2 “ Treatment Duration for 
Efficacy Analyses”.
Clarification for windowing
Section 8.1.4 “Censoring of Efficacy Data 
Based on Changes in Medications” added.
Added section to describe extra analyses 
and descriptions of censoring
Section 8.2.2 “Treatment Duration for Safety 
Analyses” added wording regarding 
treatment emergence.
Clarification regarding the definition of 
treatment emergent and windowing.
Section 8.2.4 “Safety Data Collected after the 
ED Visit”
Clarification given that separate ED visits 
will not be produced for the safety data, 
only treatment emergent data will be 
windowed as appropriate.
Section 8.4 “Algorithms for Safety 
Parameters” added
UPDRS-III subscore derivations added.


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AChEI
Acetylcholinesterase inhibitors
AE
Adverse event
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
C-CASA
Columbia- classification algorithm of suicide assessment
CFI
Cognitive Fluctuation Inventory
CGIC-DLB
Clinician Global Impression of Change in Dementia with Lewy 
Bodies
cGMP
Cyclic guanosine monophosphate
CI
Confidence interval
CIBIC-Plus
Clinician’s Interview Based Impression of Change Plus 
Caregiver Input 
CRF
Case report form
CSF
Cerebrospinal fluid
CSR
Clinical study report
C-SSRS
Columbia – Suicide Severity Rating Scale
CV
Coefficient of variation
DEMQOL
Dementia Quality of Life Measure
DEMQOL-Proxy
Dementia Quality of Life Measure by Proxy
DLB
Dementia with Lewy bodies 
DMC
Data monitoring committee
DSMB
Data safety monitoring board
ECG
Electrocardiography
eCRF
Electronic case report form
ED
Early Discontinuation
EEG
Electroencephalography


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EQ VAS
Overall health rating of EQ-5D
EQ-5D
EuroQol-5 Dimension questionnaire
EQ-5D Proxy
EuroQol-5 Dimension questionnaire by Proxy
FAS
Full analysis set
GDS
Geriatric Depression Scale
GLMM
Generalized linear mixed models
IA
Interim Analysis
ITT
Intent to treat
LP
Lumbar puncture 
LS
Least squares
MAR
Missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed-effects models for repeated measures
MMSE
Mini Mental State Examination
MNAR
Missing not at random
MoCA
Montreal Cognitive Assessment
NPI
Neuropsychiatric Inventory 
PD
Pharmacodynamic
PGx
Pharmacogenomic
PK
Pharmacokinetic
PP
Per protocol
PT
Preferred term
QALYs
Quality-adjusted life years
QD
Once daily
QoL
Quality of Life
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis system


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SCOPA-Sleep
Scales for Outcome in Parkinson’s disease-Sleep
SD
Standard deviation
SE
Standard error
SI
Système International
SOC
System organ class
TEAE
Treatment-emergent adverse event
TEMAV
Treatment-emergent markedly abnormal laboratory
TLG
Tables, listings, and graphs
UPDRS-III
Unified Parkinson Disease Rating Scale - III
WHO
World Health Organization
WHO DD
World Health Organization Drug Dictionary


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3
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results based on clinical database for 
the Eisai Protocol E2027-G000-201. PK/PD/PGx analysis and relevant endpoints will not be 
described in this SAP but will be described in separate PK/PD/PGx analysis plans.
3.1
Study Objectives
3.1.1
Primary Objectives
To determine whether E2027 is superior to placebo on the cognitive endpoint of Montreal 
Cognitive Assessment (MoCA) in subjects with dementia with Lewy bodies (DLB) after 12 
weeks of treatment
To determine whether E2027 is superior to placebo on the global clinical endpoint of 
Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) after 
12 weeks of treatment
3.1.2
Secondary Objectives
1. To determine whether E2027 is superior to placebo on the following secondary 
endpoints after 12 weeks of treatment:
1.1. Clinician Global Impression of Change in Dementia with Lewy Bodies (CGIC-
DLB)
1.2. Cognitive Fluctuation Inventory (CFI)
1.3. Mini-Mental State Examination (MMSE)
1.4. Neuropsychiatric Inventory (NPI)
2. To evaluate the safety and tolerability of E2027 in subjects with DLB
3. To characterize the population pharmacokinetics (PPK) of E2027 in subjects with 
DLB, including evaluation of the effects of intrinsic and extrinsic factors on E2027 PK
3.1.3
Exploratory Objectives
1. To explore the efficacy of E2027 compared to placebo on the following endpoints after 
12 weeks of treatment:
1.1. Scales for Outcome in Parkinson’s disease-Sleep (SCOPA-Sleep)


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1.2. Dementia-related quality of life as assessed by the Dementia Quality of Life 
Measure (DEMQOL; interview of subject) and Dementia Quality of Life Measure 
by Proxy (DEMQOL-Proxy; interview of caregiver or informant about subject)
1.3. General health status as assessed by the EuroQol-5 Dimension questionnaire (EQ-
5D; completed by subject) and EuroQol-5 Dimensions questionnaire by Proxy 
Version 1 (EQ 5D Proxy; caregiver or informant completion of report about 
subject)
To evaluate the relationship between PK exposure of E2027 and its effects on various 
efficacy and safety endpoints
To explore the PK/pharmacodynamic (PD) relationship between the exposure of E2027 in 
cerebrospinal fluid (CSF)/plasma and its effects on CSF PD biomarker endpoints, including
CSF cyclic guanosine monophosphate (cGMP), if data permit
To explore the relationship between the E2027 PD effects (including CSF cGMP) with 
E2027 effects on various efficacy endpoints, if data permit 
To explore collected pharmacogenomic (PGx) samples by investigating heterogeneity in 
clinical features of disease, including differences in baseline characteristics as well as 
response to compound (efficacy, safety and/or absorption, distribution, metabolism, and 
excretion [ADME]).  These exploratory analyses are not limited to this protocol or project.  
These findings may be used for identification and validation of new drug targets
3.2
Overall Study Design and Plan
This is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study in 
subjects with DLB who will be treated with placebo or E2027 (50 mg once daily [QD]) for 12 
weeks.  
In some of the countries selected for this study, donepezil is approved for DLB and 
acetylcholinesterase inhibitors (AChEIs) are often used as part of standard care in patients with 
DLB.  Therefore, the study design allows for add-on therapy to standard of care for DLB, 
which includes AChEI and/or memantine at stable doses, except for any prohibited 
medications specified in this protocol.  Subjects who are not receiving AChEI or memantine
are also eligible, but are not permitted to start such medications during the study.  
Randomization will be stratified based on whether subjects are on a stabilized dose of AChEI 
or not and by geographical region (ie, North America, Europe, or Japan).  Subjects will be 
randomly assigned to placebo or E2027 (50 mg QD) in a ratio of 1:1
For all subjects, study participation will comprise 2 phases:  Prerandomization and 
Randomization.  The Prerandomization Phase will last for up to 6 weeks and will include a 


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Screening Period (up to 5 weeks) and a Baseline Period (1 week).  The Randomization Phase 
will last for 16 weeks and will include a Treatment Period (12 weeks) and a Follow-up Period 
(4 weeks).
Screening will occur between Day -42 and Day -8.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Eligibility assessments at 
Screening will be conducted in tiers and subjects will need to satisfy eligibility criteria in 
each tier before proceeding to the next tier.  There are total 6 tiers. Subjects who are deemed 
eligible after passing all tiers at Screening will proceed to the Baseline Visit.
The baseline visit may take place at any time up to 7 days before the first dose of study drug 
(Day 1, ie, during Day -7 to Day -1, but should take place at least 2 weeks after the Screening 
Visit Tier 2 assessments).  
After completing study assessments at the Baseline Visit, subjects who continue to be 
eligible will proceed to the Randomization Phase, and will be randomly assigned to placebo 
or E2027 (50 mg QD).  They will be provided with study drug (placebo or E2027) to start 
administration in the morning of Day 1 at home.  They will continue to take study drug for 
12 weeks.  During the Treatment Period study visits will be conducted after 2, 4, 6, 9 and 12 
weeks on study drug.  Safety assessments will be conducted at all these visits.  Efficacy 
assessments will be performed after 6 and 12 weeks on study drug and should be performed 
at approximately the same time of the day as at the Baseline Visit whenever possible 
(preferably in the morning).  
After the Treatment Period, subjects will complete a Follow-Up Visit 4 weeks after the final 
dose of study drug.  
The end of study was the date of the last study visit for the last subject.
Early Discontinuation
Subjects who prematurely discontinue study drug for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their final dose of study drug.  The safety and 
efficacy assessments normally performed after 12 weeks of treatment will be conducted at 
the ED Visit.  In addition, subjects who discontinue study drug are expected to continue in 
the study for the originally scheduled visits, starting with next such visit that is >7 days after 
the ED Visit.  Subjects who prematurely discontinue the study should attend at least 1 
originally scheduled visit after the ED Visit.
CSF Substudy
A subset of subjects will participate in a substudy in which CSF will be collected by lumbar 
puncture (LP) during Screening and again during the Randomization Phase after 9 weeks of 
treatment on study drug.  Participation in the substudy will be voluntary.  After they have 
completed all screening assessments and are deemed eligible for the study, a baseline CSF 
sample will be collected at least 7 days before the Baseline Visit.  After they have completed 


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9 weeks of treatment, they will have a 2nd CSF sample collected.  The CSF samples will be 
collected in the morning at approximately the same time, either in the fasted state (preferred) 
or at least 2 hours after breakfast.
As data permit, CSF cGMP will be assayed to evaluate the PD effects of E2027 in these 
subjects with DLB.  Other CSF PD biomarkers related to DLB or E2027 PD effects may also 
be assayed if appropriate.  CSF E2027 concentrations will also be determined.
Data Safety Monitoring Board
An independent data safety monitoring board (DSMB) will convene at regular intervals to 
monitor the overall safety of the study and to make recommendations to the sponsor related 
to study safety as appropriate.  The DSMB will be asked to review the cumulative safety data 
up to the date identified to make a determination if the study is safe to proceed unchanged or 
to provide recommendations to the sponsor as to how to proceed.  The study will proceed, 
including randomization of additional subjects, during DSMB safety reviews.  Details will be 
provided in the DSMB Charter.
4
DETERMINATION OF SAMPLE SIZE
The MoCA scale was assessed in DLB subjects and reported by Biundo et al. (2016).  The 
observed mean change from baseline in the MoCA total score at 1 year in this report is -1.04 
points and the corresponding standard deviation (SD) is 1.32 points.  An estimation of the 
mean change from baseline in the MoCA total score at 3 months is approximately -0.26 
points using linear interpolation.  It is assumed that E2027 would improve the MoCA total 
score as compared with baseline and achieve a mean treatment difference of approximately 
0.6 points between E2027 and placebo at 12 weeks.  The SD of change from baseline in the 
MoCA total score at 3 months is expected to be smaller than that at 1 year.  A conservative 
estimate of the SD of change from baseline in the MoCA total score is 1.3 points at 12 
weeks.
In a 12-week donepezil monotherapy study in subjects with DLB (E2020-J081-431), the 
estimated proportional odds ratio based on the CIBIC-Plus scale for donepezil 10 mg relative 
to placebo was 6.14.  It is assumed that E2027 would achieve a proportional odds ratio of 
2.607 relative to placebo (ie, 42% of the effect size observed in the above donepezil study). 
With 80 subjects completing per arm (for 91 randomized subjects per arm, assuming a 12% 
dropout rate), this study will have approximately 80% power to detect the above effect sizes 
(ie, mean treatment difference of approximately 0.6 points based MoCA total score and 
proportional odds ratio of 2.607 based on CIBIC-Plus scale for E2027 relative to placebo) in 
both co-primary endpoints simultaneously.  Therefore, the total sample size of 182 
randomized subjects is planned, assuming a 12% dropout rate.


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The MoCA total score on blinded study data shows SD is 3 points, to keep 80% power and 
the effect size of 0.46 with 80 subjects completing each arm, the treatment difference would 
need to be 1.4. A treatment difference of 1.4 has been shown with blinded study data to be 
similar to a one unit change in CIBIC-Plus, which is clinically meaningful.
CSF Substudy
Participation in the CSF substudy is voluntary.  It is estimated that approximately 30% of 
subjects will participate in the CSF substudy.  If the dropout rate in the CSF substudy is 12%, 
20%, or 50%, then the number of subjects having final CSF assessment would be 
approximately 48, 44, or 27, respectively.  The estimated standard deviation of percent 
change from baseline of cGMP concentrations after 9 weeks of treatment from pooled 
subjects in the CSF substudy is approximately 130%.  The width of the 95% CI of the mean 
difference of percent change from baseline of cGMP concentrations after 9 weeks of 
treatment between E2027 and placebo for the 3 different sample sizes above would be 
approximately 74%, 77%, or 96%, respectively.  Since mean percent change from baseline of 
cGMP concentrations after 9 weeks of treatment in the E2027 and placebo groups are 
expected to be approximately 200% and 5%, respectively, the sample size of the CSF 
substudy would be adequate to detect the mean difference of percent change from baseline of 
cGMP concentrations after 9 weeks of treatment between E2027 and placebo groups.
5
STATISTICAL METHODS
All statistical tests will be 2-sided at the 5% significance level unless otherwise stated. All 
descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, minimum, maximum and number of subjects with non-missing data.  
Categorical variables will be summarized as number (percentage) of subjects.
5.1
Study Endpoints
The details of calculating each efficacy endpoint are presented in Section 8.3 ALGORITHMS 
FOR EFFICACY PARAMETERS. The details of calculating each QoL endpoint are presented 
in Section 5.7 OTHER ANALYSES.
5.1.1
Primary Endpoints
Change from baseline in the MoCA total score at 12 weeks of treatment 
CIBIC-Plus scale at 12 weeks of treatment 
5.1.2
Secondary Endpoints
CGIC-DLB scale at 12 weeks of treatment

Change from baseline at 12 weeks of treatment in the following endpoints: 


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o
CFI score
o
MMSE total score
o
NPI total score, subscores and caregiver or informant distress score
Safety and tolerability of E2027 as measured by
o
Incidence of adverse events including severe AEs, serious AEs, AEs resulting in
discontinuation
o
Incidence of orthostatic hypotension and orthostatic tachycardia 
o
Incidence of markedly abnormal laboratory values and shifts from baseline of 
laboratory values
o
Incidence of abnormal ECG parameters and abnormal ECG findings
o
Incidence of suicidality based on C-SSRS
o
Changes from baseline in the total score of UPDRS-III
5.1.3
Exploratory Endpoint(s) 

Change from baseline at 12 weeks of treatment in the following endpoints: 
o
SCOPA-Sleep total score and subscores

Change from baseline at 12 weeks of treatment in the following endpoints:
o
Total score and domain scores of the DEMQOL and DEMQOL-Proxy
o
EQ-5D utility score and EQ-5D health status rating

Percentage change from baseline in CSF cGMP concentrations after 9 weeks of treatment

CIBIC-plus sub-items (Attention, Orientation, Memory, etc) rating
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Randomized Set is the group of subjects who are randomized to study treatment.
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 post dose safety assessment. The Safety Analysis Set will be used in the 
statistical analyses for safety. In the event that a subject received study drug different from 
the one to which this subject was randomized, the subject’s safety data will be analyzed “as 
actually treated” for the safety analyses.
The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose 
of study drug and have baseline and at least 1 post dose primary efficacy measurement. In the 
event that a subject received study drug different from the one to which this subject was 


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randomized, the subject’s efficacy data will be analyzed “as randomized” for the FAS 
analyses.
The PK Analysis Set is the group of subjects with at least 1 quantifiable E2027 serum 
concentration with a documented dosing history.
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1
PD parameter.
The Per Protocol (PP) Analysis Set is the subset of subjects in the Full Analysis Set who 
sufficiently complied with the protocol. It may include subjects who complete certain pre-
specified minimal exposure to the treatment and have no major protocol violations such as 
wrong diagnosis, error in treatment assignment, use of prohibited medication and poor 
compliance. The precise reasons for excluding subjects from the Per Protocol Set will be 
fully defined and documented before database lock, see Section 5.2.3. 
5.2.2
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF. The distribution of the number of randomized subjects by each site will
be summarized by treatment group and total.  
Study Completion: the number (percent) of randomized and treated subjects who completed
the study and who discontinued from the study will be summarized according to the primary
reason for discontinuation and secondary reason(s) for discontinuation, based on data
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be
presented by treatment group, overall and by stratification factors.
Completion of Study Treatment: the number (percent) of randomized and treated subjects
who completed study treatment and who discontinued from study treatment will be
summarized according to the primary reason for discontinuation and also according to
secondary reason(s) for discontinuation, based on data reported on Early Discontinuation
from Study Drug eCRF.  The number (percent) will be presented by treatment group
and total, overall and by stratification factors. Subjects who discontinued study treatment but 
were followed up for efficacy assessments after treatment discontinuation will also be 
summarized. 
5.2.3
Protocol Deviations
Major protocol deviations for the PP Analysis Set include:

Subject did not meet Inclusion Criterion #2, which was: 2. Meet criteria for probable 
DLB (e.g. date of diagnosis of DLB missing).

Subject met Exclusion Criteria #6, which was: 6. GDS score >8.


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
Subject received incorrect study treatment for more than 6 weeks. 

Subject initiated prohibited medications used in the treatment of dementia during the 
12 weeks treatment period.
Subject had poor compliance with study treatment (e.g., overall compliance is <80%).
In addition, subjects with treatment duration less than 6 weeks will be excluded from the PP 
Analysis Set. 
The number (percentage) of subjects excluded from PP analysis will be summarized by reason 
for exclusion and treatment group. A listing of subjects excluded from PP analysis will be 
provided along with the description of reason for exclusion.  
5.2.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics for the Safety Analysis Set, FAS and PP Analysis 
Set will be summarized for each treatment group using descriptive statistics, overall and by 
stratification factors.  Continuous demographic and baseline variables include age, age at 
diagnosis, age at onset, years since onset of symptoms, MoCA total score, NPI total score, 
NPI-4 score, NPI-10 score, NPI subscores, MMSE total score, CFI score, body weight, height, 
disease duration, baseline UPDRS part III score, CSF cGMP, EQ-5D, EQ-5D proxy, EQ-5D 
VAS score, EQ-5D VAS score proxy, DEMQOL, DEMQOL proxy, SCOPA – Sleep Overall, 
SFQ Score, average time per day for caregiver to spend with patient, and average days per 
week for caregiver to spend with patient; categorical variables include age subgroup (< 65, ≥
65 to <80, ≥80), sex, race, ethnicity, region, CIBIS Plus, MMSE total score subgroup (14-19, 
20-26), C-CASA, C-SSRS not completed, ongoing treatment with AChEIs (yes or no),
treatment with memantine (yes or no), treatment with AChEI and/or memantine (none, AChEI 
only, memantine only, AChEI and memantine), Hoehn & Yahr stage, relationship of caregiver 
to patient, caregiver reside with the patient (Yes or Not), have each clinical core feature 
(hallucination, fluctuation, parkinsonism, RBD) (Yes or Not), and have 2 or more core clinical 
feature or have only 1 clinical feature (Appendix 1 of protocol: Diagnostic Criteria for Probable 
Dementia With Lewy Bodies (DLB)), have each clinical supportive feature, have each 
indicative biomarker. Where Screening values are also collected, these may be summarized 
also.
Where the date of diagnosis only contains the year of diagnosis, the age of diagnosis will use 
the year of diagnosis – year of birth.
MEDICAL HISTORY
The medical history verbatim descriptions (investigator terms from the CRF) will be classified 
into standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Medical history will be coded to the MedDRA (Version 19.0 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database.


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The number (percent) of subjects will be presented by SOC and PT for each treatment group.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD). The number (percentage) 
of subjects who took prior and concomitant medications will be summarized on the Safety 
Analysis Set by treatment group, Anatomical Therapeutic Chemical (ATC), and WHO DD 
preferred term.  Prior medications are defined as medications that stopped before the first dose 
of study drug.  Concomitant medications are defined as medications that (1) started before the 
first dose of study drug and were continuing at the time of the first dose of study drug, or (2) 
started on or after the date of the first dose of study drug and continued up to the last dose.
Prior and concomitant therapies for DLB and those for non-DLB will be summarized 
separately, the summaries showing therapies for DLB will also be summarized separately 
based on AChEI stratification. 
The number (percentage) of subjects with changes in AChEI and non-AChEI restricted 
medications will be summarized by treatment group, Anatomical Therapeutic Chemical 
(ATC), and WHO DD preferred term.
5.2.6
Treatment Compliance
Percent compliance will be calculated for the FAS as follows:
Compliance = Total number of tablets dispensed – Total number of tablets returned x 100%
                                              
Planned Total number of tablets to be taken  
Overall compliance with study medication will be summarized using descriptive statistics 
(median, mean, standard deviation, minimum, maximum, and number of subjects with non-
missing data) for each treatment group.   Subjects will also be categorized by compliance 
criteria <50%, ≥50%-<80%, ≥80%-≤100%, >100% - ≤120%, >120% and missing. The 
maximum of planned total number of tablets to be taken will be 84.
5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
This is a multi-center, international study conducted in three geographic regions, i.e. United
States, Europe, and Japan. Sites will be pooled into the three regions, in order to have sufficient 
number of subjects per treatment group.  
5.3.2
Adjustments for Covariates of Interest
The baseline value will be used as a covariate, and stratification variables (on AChEI or not 
and geographical region (US, Europe, Japan)) will be used as factors in the efficacy models 


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for analysis of continuous endpoints. Baseline for the primary and secondary efficacy 
endpoints is defined as the last pre-treatment assessment. 
5.3.3
Multiple Comparisons/Multiplicity
There are 2 co-primary endpoints, change from baseline in the MoCA total score at 12 weeks 
and CIBIC-Plus score at 12 weeks. Overall there are 2 null hypotheses to be tested in the 
primary efficacy analysis. The study will be considered positive if statistically significant 
improvement (at level of 0.05 (2-sided) or 0.025 (1-sided)) is observed in both co-primary 
endpoints in E2027.
5.3.4
Examination of Subgroups
The co-primary and secondary efficacy endpoints, treatment-emergent adverse events,
treatment-emergent markedly abnormal laboratory values will be examined for the following 
subgroups:

On AChEI at baseline (Yes or Not)

Region (US, Europe, Japan)

Receiving memantine at baseline (Yes or No)

AChEI and/or memantine at baseline (none, AChEI only, memantine only, 
AChEI+memantine)

Hoehn & Yahr stage (0&I&II or III)
In addition, the co-primary and secondary efficacy endpoints will also be examined by the 
following subgroups:

Baseline MMSE subgroup (>14 total score <19, >20 total score <26)  

Age (<65, ≥ 65 to <80, ≥80)

NPI hallucination sub-item score (≥median/<median)

Caregiver’s time per week to spend with subject (≥median/<median)
For other demography and safety data (vital signs, ECGs, etc), the summaries will be 
subgrouped by stratification factors, as appropriate.
Where subgroups are small, summaries and analyses will be produced, caution will be used in 
the interpretation of those subgroups.


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5.3.5
Handling of Missing Data, Drop-outs, and Outliers
5.3.5.1 Efficacy 
For non-EMA registration, for primary and secondary efficacy endpoints, there will be no 
imputation of missing value. MMRM and GLMM will be used to analyze repeated measures 
of continuous and ordinal data, respectively.
For EMA registration, for co-primary efficacy endpoint MoCA and all continuous secondary 
efficacy endpoints, there will be no imputation of missing value at individual level. The 
statistical estimate will be calculated based on the mean imputation method proposed by 
Mehrotra et al (2017). For EMA registration, the missing co-primary efficacy endpoint CIBIC-
Plus and ordinal secondary efficacy endpoint will be imputed using control-based pattern
imputation at subject level (Yuan 2014).
The date of change in AChEIs stable dose during treatment period, Screening and 12 weeks 
prior to Screening will be used in the sensitivity analysis to determine the censoring time. In 
case the date of change in AChEIs stable dose is missing, the missing date will be imputed 
similarly to missing start date of concomitant medication but replacing the First Dose Date by 
Last Visit Date before the change in AChEIs stable dose as reference date in the imputation. 
Please refer to AChEIs Stable Dose CRF page to determine the last visit date before the change 
in AChEIs stable dose.
Where non-AChEI restricted medications are changed during the 
treatment period, Screening and 4 weeks prior to Screening (12 weeks prior to Screening for 
memantine), the above method will be used similarly.
Post-ED data will be included in all the analyses.  
5.3.5.2 Safety
The methods for handling missing start and end dates are described in standard Eisai SDTM 
Domain Mapping Specifications Template (Appendix 13.4) and documented in SDTM+
specification. 
All the listings will display the original missing values.
5.3.6
Other Considerations
Not Applicable.
5.4
Efficacy Analyses
5.4.1
Primary Efficacy Analyses
The treatment effect of interest will be the efficacy as measured by co-primary endpoints that 
would be observed at 12 weeks regardless of whether or when the assigned treatment was 
discontinued due to adverse event, lack of efficacy or any other events related to treatment or 


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study outcome.  The target population is DLB subjects defined by inclusion/exclusion 
criteria.
There are 2 co-primary efficacy endpoints, change from baseline in the MoCA total score at 
12 weeks and CIBIC-Plus scale at 12 weeks.  Overall there are 2 null hypotheses (H0) to be 
tested in the primary analysis:  
H01:  There is no difference in the mean change from baseline in the MoCA total score at 
12 weeks between E2027 and placebo.
H02:  The proportional odds ratio based on CIBIC-Plus scale at 12 weeks between E2027 and 
placebo is equal to 1.
The corresponding 2 alternative hypotheses are that there is a difference in the mean change 
from baseline in MoCA total score at 12 weeks in this co-primary endpoint between E2027 
and placebo and the proportional odds ratio based on CIBIC-Plus scale at 12 weeks between 
E2027 and placebo is not equal to 1. The study will be considered positive if statistically 
significant improvement (at level of 0.05 (2-sided) or 0.025 (1-sided)) is observed in both co-
primary endpoints in E2027. 
Due to correspondence with the FDA during the study, separate analyses will be performed 
for the non-EMA and EMA registrations, the endpoints remain identical.  
Non-EMA Analyses
Co-primary Analysis of Change from Baseline in the MoCA Total Score at 12 Weeks
for non-EMA registration 
Change from baseline in the MoCA total score at 12 weeks will be analyzed using MMRM. 
The MMRM model will include baseline variable (corresponding to the response variable in 
the model) as a covariate, treatment group, visit (Week 6 and Week 12), randomization 
stratification variables (receiving AChEI or not, geographical region [North America, 
Europe, Japan]), baseline variable-by-visit interaction, and treatment group-by-visit 
interaction as fixed effects.  An unstructured covariance matrix will be used to model the 
covariance of within subject effect; if MMRM fails to converge then a covariance structure 
with fewer parameters from the following list will be employed according to the prespecified 
order in the list until the MMRM converges.  The list of covariance structure will include 
Heterogeneous Toeplitz, Toeplitz, Heterogeneous Compound Symmetry, and Compound 
Symmetry. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom when unstructured covariance matrix is used. If MMRM fails to converge 
and a structured covariance matrix is used, the empirical method will be used to compute
variance-covariance matrix of the fixed-effects parameters (sandwich estimator).  
Sensitivity Analysis of Change from Baseline in the MoCA Total Score at 12 Weeks for 
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A sensitivity analysis will be produced to repeat the primary analysis for MoCA but to censor 
data after changes in AChEI medications.  
Co-primary Analysis of the CIBIC-Plus Scale at 12 Weeks for non-EMA registration
CIBIC-Plus scale at 12 weeks will be analyzed using GLMM. The GLMM model will 
include treatment, visit, randomization stratification variables (receiving AChEI or not, 
geographical region [North America, Europe, Japan]), and treatment x visit as fixed effects.  
The model will be fitted using GLMM with a multinomial distribution and a cumulative logit 
link function.  If the proportional odds assumption is contradicted (p < 0.05 in Score Test for 
the Proportional Odds Assumption) by the observed data in either the entire population or 
any stratum, the GLMM method will be replaced by the nonparametric van Elteren test
adjusting 2 randomization stratification variables (on stabilized AChEI dose or not; 
geographical region [North America, Europe, Japan]). 
Sensitivity Analysis of the CIBIC-Plus Scale at 12 Weeks for non-EMA registration
A sensitivity analysis will be produced to repeat the primary analysis for CIBIC-Plus but to 
censor data after changes in both AChEI and non-AChEI medications.
EMA Analyses
Co-primary Analysis of Change from Baseline in the MoCA Total Score at 12 Weeks
for EMA registration
The change from baseline of MoCA total score for E2027 dose compared to placebo will be 
analyzed using the approach proposed by Mehrotra et al (2017) with slight modification 
based on reasons for missing data.  The following is a list of the missing reasons and their 
missing mechanisms: 
Data not observed because of dropouts (primary reason) due to AEs, lack of efficacy or any 
other intercurrent events related to treatment or study outcome will be considered as missing 
not at random (MNAR).  Where there are other/secondary reasons for dropout that relate to a 
new drug being taken in response to an AE, this will also be counted as MNAR, even if the 
primary reasons for drop out may not be classed as not related to treatment or outcome.
Where data are not done with the patient continuing study, the data will be considered 
MNAR where reasons for missingness are related to AEs, the subject is sleepy/drowsy, the 
subject is delirious, or the subject refused/declined (where refusal was not related to 
withdrawal of consent).
Data not observed because of dropouts due to intercurrent events definitely not related to 
treatment or outcome (eg, withdraw consent due to logistical problems) will be considered as 
missing at random (MAR).  Where data are not done with the patient continuing study, the 
data will be considered MAR where reasons for missingness are not related to AEs, the 


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subject is sleepy/drowsy, the subject is delirious, or the subject refused/declined, except if the 
refusal was due to withdrawal of consent. 
The missing endpoint values considered as MAR can be imputed using condition distribution 
from the observed endpoint values and therefore can be handled by MMRM analysis 
assuming MAR. The mean of missing endpoint values in the E2027 treatment group 
considered as MAR can be viewed as implicitly imputed using the estimated means of 
endpoint values of completers and all subjects through MMRM analysis including 
completers and subjects with missing values considered as MAR in the E2027 treatment 
group. The mean of missing endpoint values in E2027 treatment group considered as MNAR 
will be imputed by the mean of the overall endpoint distribution under placebo as described 
next.  The mean of the overall endpoint distribution under placebo will be obtained using 
mixed effects model of repeated measures (MMRM) within placebo group assuming MAR. 
Test statistics and the p-value will be obtained as described by Mehrotra, et al. (2017). In the 
presence of subjects with missing endpoint values considered as MAR, the superscript of 
“drop” refers to “subjects with missing endpoint values considered as MNAR” and the 
superscript of “comp” refers to “completers and subjects with missing endpoint values 
considered as MAR”.
Sensitivity Analysis of Change from Baseline in the MoCA Total Score at 12 Weeks for 
EMA registration
A sensitivity analysis will be produced to repeat the primary analysis for MoCA but to censor 
data after changes in AChEI medications.  For this the following missing mechanism will be 
added to the above reasons in the primary analysis
The effect had rescue medication not been made available to subjects prior to week 12 is not 
observable for subjects who initiated prohibited or restricted rescue medication.  For these 
subjects, the data collected after initiation of prohibited rescue medication are assumed to 
contain no treatment effect in the E2027 treatment group.  Technically, response data 
collected after initiation of new AChEIs or after any change in concomitant AChEIs stable 
dose will be treated as MNAR such that response data treated as MNAR in the E2027 
treatment group would be imputed by the mean response in the placebo treatment group as 
described by the imputation method below.
In order to generate inputs for proposed primary and sensitivity analyses for the EMA 
registration, a MMRM will be used in separate MMRM analyses for each treatment group for 
all randomized subjects as well as completers assuming MAR for both treatment groups.  
The model will be adjusted for baseline MoCA, visit (Week 6 and Week 12), randomization 
stratification variables (receiving AChEI or not, geographical region [North America, 
Europe, Japan]), and baseline MoCA × visit as fixed effects.  An unstructured covariance 
matrix will be used to model the covariance of within subject effect; if MMRM fails to 
converge then a covariance structure with fewer parameters from the following list will be 
employed according to the prespecified order in the list until the MMRM converges.  The list 
of covariance structure will include Heterogeneous Toeplitz, Toeplitz, Heterogeneous 


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Compound Symmetry, and Compound Symmetry. The Kenward-Roger approximation will 
be used to estimate the denominator degrees of freedom when unstructured covariance matrix 
is used. If MMRM fails to converge and a structured covariance matrix is used, the empirical 
method will be used to compute variance-covariance matrix of the fixed-effects parameters 
(sandwich estimator). The values of baseline MoCA will be adjusted using the overall 
baseline mean of all study subjects in computing least square (LS)-means.
Co-primary Analysis of the CIBIC-Plus Scale at 12 Weeks for EMA registration
The primary analysis of the CIBIC-Plus scale at 12 weeks will be based on control-based 
pattern imputation at subject level (Yang, 2014).  The CIBIC-Plus scale at 12 weeks will be 
imputed as an ordinal response variable. The same missing reasons and corresponding 
missing mechanism as in the analysis of change from baseline in MoCA total score will be 
used in this analysis.  Only the missing ordinal responses in E2027 treatment group 
considered as MNAR will be imputed by ordinal responses observed in the placebo group 
using a pattern-mixture model approach under MNAR assumption.  Other missing ordinal 
responses will be imputed assuming MAR.  This can be implemented using multiple 
imputation in two steps: Step 1: impute E2027 dropouts considered as MAR and placebo 
dropouts using multiple imputations assuming MAR, e.g., generate N (N = 100 or larger) 
datasets; Step 2: impute the E2027 dropouts considered as MNAR using placebo data and a 
pattern-mixture approach under the MNAR assumption for each above imputed dataset in 
Step 1. In each step, the multiple imputations will be conducted using Proc MI implemented 
in SAS 9.4. The logistic regression method of classification variables will be specified to 
impute missing values for CIBIC-Plus scale. In Step 2, an additional MNAR statement will 
be used to complete the control-based pattern imputation at subject level.
The CIBIC-Plus scale at 12 weeks (observed or imputed) will be analyzed using the 
proportional odds model, a special case of generalized linear mixed models (GLMM), in 
multiply imputed data sets.  The results obtained from all multiply imputed data sets will be 
combined for overall inference using Rubin's rules.  The GLMM model will include 
treatment, randomization stratification variables (receiving AChEI or not, geographical 
region [North America, Europe, Japan]) as fixed effects.  The model will be fitted using 
GLMM with a multinomial distribution and a cumulative logit link function.  The 
proportional odds ratio estimate between E2027 and placebo, the corresponding 95% CI and 
P-values will be presented.  
Sensitivity Analysis of the CIBIC-Plus Scale at 12 Weeks for EMA registration
A sensitivity analysis will be produced to repeat the primary analysis for CIBIC-Plus but to 
censor data after changes in both AChEI and non-AChEI medications.  For this the following 
missing mechanism will be added to the above reasons in the primary analysis


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The effect had rescue medication not been made available to subjects prior to week 12 is not 
observable for subjects who initiated prohibited or restricted rescue medication.  For these 
subjects, the data collected after initiation of prohibited rescue medication are assumed to 
contain no treatment effect in the E2027 treatment group.  Technically, response data 
collected after initiation of new AChEIs or non-AChEIs prohibited or restricted medications 
(as specified in Concomitant Drug/Therapy section in the protocol) or after any change in 
concomitant AChEIs or non-AChEIs stable dose will be treated as MNAR such that response 
data treated as MNAR in the E2027 treatment group would be imputed by the mean response 
in the placebo treatment group as described by the imputation method below.
A sensitivity analysis that excludes all subjects with changes in AChEI or non-AchEI 
restricted medications will also be performed.
If the proportional odds assumption is contradicted (p < 0.05 in Score Test for the 
Proportional Odds Assumption) by the observed data in either the entire population or any 
stratum, the GLMM method will be replaced by the nonparametric van Elteren test in both 
primary analysis and sensitivity analysis.  The CIBIC-Plus scale at 12 weeks will be analyzed 
using van Elteren test adjusting 2 randomization stratification variables (on stabilized AChEI 
dose or not; geographical region [North America, Europe, Japan]).  The H0 corresponding to 
the van Elteren test is that there is no difference in the location of distribution of the CIBIC-
Plus scale at 12 weeks between E2027 and placebo.  The corresponding alternative 
hypothesis is that there is a difference in the location of distribution of the CIBIC-Plus scale 
at 12 weeks between E2027 and placebo.
Supplementary Analysis for both non-EMA and EMA registrations
Subgroup (eg, region, age group, baseline AChEI status, baseline memantine status, and 
baseline MMSE subgroup) analyses will be performed for the subgroups defined in Section 
5.3.4.  The treatment effect within each subgroup and corresponding 95% CI for each co-
primary endpoint will be summarized and also depicted using forest plot.
The treatment effect will be also examined using PP Analysis Set for each co-primary 
endpoint and analysis. 
Descriptive statistics and graphical presentation for each co-primary endpoint will be 
provided.
Table 4
Primary Efficacy Analyses
Score
Analysis for non-EMA
Registration
Analysis for EMA 
Registration
MoCA
Primary 
MMRM
Control based mean 
imputation with Mehrotra


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Sensitivity
As primary, but censor 
changes in AChEI medication
As primary, but censor 
changes in AChEI medication
Supplementary
As primary, subgroups
As primary, subgroups
As primary, Per Protocol 
Analysis Set
As primary, Per Protocol 
Analysis Set
CIBIC-
Plus
Primary 
GLMM
Proportional odds model with 
control-based pattern 
imputation
Sensitivity
Censor changes in both 
AChEI and non-AChEI 
medications
Censor changes in both 
AChEI and non-AChEI 
medications
Exclude subjects with 
changes/new AChEI and non-
AChEI restricted medications
Exclude subjects with 
changes/new AChEI and non-
AChEI restricted medications
Supplementary
As primary, subgroups
As primary, subgroups
As primary, Per Protocol 
Analysis Set
As primary, Per Protocol 
Analysis Set
5.4.2
Secondary Efficacy Analyses
Table 5
Secondary Efficacy Analyses
Score
Analysis for non-EMA
Registration
Analysis for EMA 
Registration
CGIC-
DLB
Secondary 
analysis
GLMM
Proportional odds model 
with control-based pattern 
imputation
Additional 
secondary 
analysis
Proportional odds model 
with control-based pattern 
imputation
GLMM
CFI
Secondary 
analysis
MMRM
Control based mean 
imputation with Mehrotra
Additional 
secondary 
analysis
Control based mean 
imputation with Mehrotra
MMRM


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MMSE
Secondary 
analysis
ANCOVA and multiple 
imputation (MI) assuming 
MAR
ANCOVA and control-based 
pattern imputation
NPI
Secondary 
analysis
MMRM
Control based mean 
imputation with Mehrotra
Additional 
secondary 
analysis
Control based mean 
imputation with Mehrotra
MMRM
MoCA
Additional 
secondary 
analysis
Control based mean 
imputation with Mehrotra
MMRM
CIBIC-
Plus
Additional 
secondary 
analysis
Proportional odds model 
with control-based pattern 
imputation
GLMM
Table 5 details the analyses for the secondary endpoints.  Further details are described below.
The CGIC-DLB scale will be analyzed as ordinal response data in a manner similar to the 
primary analysis of co-primary endpoint based on CIBIC-Plus, according to both methods for 
non-EMA and EMA registrations.  
CFI is a continuous variable and will be analyzed in a manner similar to the primary analysis 
of co-primary endpoint based on MoCA, according to both methods for non-EMA and EMA 
registrations.  
For the non-EMA registration, MMSE will be analyzed using ANCOVA with MI assuming 
MAR.  For the EMA registration, MMSE will be analyzed using ANCOVA with control-
based pattern imputation at subject level for missing data handling (Yang Yuan, Paper 
SAS270-2014, SAS Institute Inc.).  The ANCOVA model will include corresponding 
baseline as a covariate, with treatment group and randomization stratification variables as 
factors.  
NPI will be analyzed in a manner similar to the primary analysis of co-primary endpoint based 
on MoCA, according to both methods for EMA, and non-EMA registrations.
The details of calculating all efficacy endpoints are presented in Section 8.3 ALGORITHMS 
FOR EFFICACY PARAMETERS.
Additional secondary efficacy analyses will be performed with or without inclusion of efficacy 
data collected after treatment discontinuation: 


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
For the non-EMA registration, the change from baseline in the MoCA total score at 12 
weeks will be analyzed using the control based mean imputation with Mehrotra as 
described above in Section 5.4.1 for the primary analysis for EMA registration.  This 
analysis will be repeated for the CFI and NPI.

For the EMA registration, the change from baseline in the MoCA total score at 12 
weeks, change from baseline in the MoCA total score at Follow-up visit and other 
continuous variables will be analyzed using MMRM, as described above in Section 
5.4.1 for the primary analysis for non-EMA registration.  This analysis will be repeated 
for the CFI and NPI.

For the non-EMA registration, the CIBIC-Plus scale at 12 weeks and other ordinal 
response variable (CGIC-DLB) will be analyzed using Proportional odds model with 
control-based pattern imputation, as described above in Section 5.4.1 for the primary 
analysis for EMA registration. 

For the EMA registration, the CIBIC-Plus scale at 12 weeks and other ordinal response 
variable (CGIC-DLB) will be analyzed using GLMM, as described above in Section 
5.4.1 for the primary analysis for the non-EMA registration.  
5.4.3
Exploratory Efficacy Analyses
The sleep endpoint (SCOPA-Sleep total score and subscores) will be analyzed in a manner 
similar to co-primary endpoint based on MoCA (according to both methods for non-EMA and 
EMA registration).  Endpoints based on CIBIC-plus sub-items (Attention, Orientation, 
Memory, etc) rating will be analyzed in a manner similar to co-primary endpoint based on 
CIBIC-plus in the additional secondary analysis (GLMM,). The analyses of quality of life 
endpoints are described in Section 5.7 Other Analyses. MoCA subscores (Attention Vigilance, 
Abstraction Score, Orientation Score, Delayed Recall Uncued Score, Language Total, Naming 
Score and Visuospatial/Executive Score) will also be analyzed similarly to the total score in 
the primary analysis (according to both methods for non-EMA and EMA registration).
If data permit, the relationship between E2027 PD effects on CSF cGMP (and other 
biomarkers) and various efficacy endpoints will be explored using correlation analysis. The 
association between individual CSF cGMP concentration data and individual efficacy data 
within each treatment group will be examined through scatter plots.  The scatter plots including 
the Pearson correlation coefficient and Spearman correlation coefficient will be produced for 
each treatment group for percentage change from baseline in CSF cGMP concentrations after 
9 weeks of treatment and change from baseline at 12 weeks of treatment of the following 
efficacy endpoints:
MoCA total score and subscores
NPI total score, subscores and caregiver distress score


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MMSE total score
CFI score
CIBIC-plus rating (1 – 7) as continuous variable.
Linear models within each treatment group may be fitted to further quantify the relationship 
between the changes in efficacy endpoints and the percent changes in CSF cGMP 
concentrations in case the above scatter plots suggested that the percent changes in CSF 
cGMP concentrations at 9 weeks of treatment may be predictive to later changes in efficacy 
endpoints.
5.5
Pharmacokinetic, Pharmacodynamic, and
Pharmacogenomic/Pharmacogenetic Analyses
The PK Analysis Set will be used for E2027 concentration listings and for summaries of 
E2027 concentrations in plasma and CSF by visit.  A population PK approach will be used to 
characterize the plasma PK of E2027. For this approach, PK data from this study will be 
pooled with relevant data from Phase 1 studies.  The PD Analysis Set will be used for the 
summaries and analyses of CSF PD biomarkers.  The percentage change from baseline in 
CSF cGMP and any other PD biomarkers after at least 9 weeks of treatment with study drug 
post randomization will be analyzed and presented graphically.  Summary statistics for CSF 
PD biomarkers will be summarized by visit If data permit, a population PK/PD approach will 
be used to characterize the relationship between plasma and/or CSF exposures to E2027 and 
CSF PD biomarker levels.  Further details on analyses of pharmacokinetic/pharmacodynamic 
data will be described in a separate PK/PD analysis plan.
Analyses of pharmacogenomic data will be described in a separate PGx analysis plan.
5.6
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs, 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, and out-of-
range vital signs, suicidality (C-SSRS), UPDRS-III, along with change from baseline in 
laboratory safety test variables, ECGs, and vital sign measurements (including orthostatic 
changes) will be summarized by treatment group. 
Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.
5.6.1
Extent of Exposure
Extent of exposure will be summarized by categories of cumulative weeks as well as by 
categories of duration of exposure.  The number and percent of subjects for each exposure 
category will be presented by treatment group. Duration of exposure is the number of days 
between the date the subject received the first dose of study drug and the date the subject 
received the last dose of study drug and will be summarized using descriptive statistics for 


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continuous variable by treatment group. Overall exposure (number of subject-weeks) is 
defined as summation over all subjects’ exposure durations and will be summarized by 
treatment group, overall and by stratification factors.
5.6.2
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 21.0 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database.
A treatment-emergent AE (TEAE) is defined as an AE that emerged during treatment or 
within 28 days following the last dose of study drug, having been absent at pretreatment 
(Baseline) or
●
Reemerged during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 
●
Worsened in severity during treatment relative to the pretreatment state, when the AE 
was continuous.
Only those AEs that are 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, overall and by 
stratification factors, on the Safety Analysis Set.  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 (related and not 
related).
Summaries of common TEAEs will be produced.
TEAEs will be summarized by the following subgroups: on AChEI at baseline (Yes or Not), 
region (US, Europe, Japan), receiving memantine (yes or no), age (age < 65, 65 ≤ age <  80, 
age ≥80 years) and Hoehn & Yahr stage (0&I&II or III), receiving AChEI and/or memantine 
(none, AChEI only, memantine only, AChEI+memantine).
A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each treatment group, overall and by 
stratification factors. A subject data listing of all SAEs will be provided.


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The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group, overall and by 
stratification factors. A subject data listing of all AEs leading to discontinuation from study 
drug will be provided.
TEAEs associated with special situations such as overdose, misuse, abuse, medication error, 
pregnancy, TEAEs with signal of possible drug abuse potential, and those requiring additional 
Medical Monitor follow-up will be listed and summarized similarly.
A summary of non-treatment emergent AEs will be produced, these are adverse events which 
occurred >28 days after final dose of study drug.
5.6.3
Laboratory Values
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in protocol 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,treatment group, overall and by stratification factors, using descriptive 
statistics.  Qualitative parameters listed in protocol 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 
shift table that compares the baseline LNH classification to the LNH classification at each 
post-baseline visit and at the end of treatment.  Similar shift tables will be used to compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
The Sponsor’s Grading for Laboratory Values (see Appendix 13.1) presents the criteria that 
will be used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV).  Except for phosphate, a laboratory value was determined to be a treatment-
emergent markedly abnormal value (TEMAV) if the post-baseline grade increased from 
baseline and the post-baseline grade was greater than or equal to 2.  For phosphate, a laboratory 
value was determined to be a treatment-emergent markedly abnormal value (TEMAV) if the 
post-baseline grade increased from baseline and the post-baseline grade was greater than or 
equal to 3.  When displaying the incidence of TEMAVs, each subject will be counted once in 
the laboratory parameter high and in the laboratory parameter low categories, as applicable.


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5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiration rate, temperature and weight) and changes from baseline for above parameters as 
well as orthostatic changes for diastolic and systolic blood pressure, pulse will be presented by 
visit and treatment group, overall and by stratification factors.
Orthostatic hypotension is defined based on the following criteria per protocol:
Drop in standing systolic blood pressure >=20 mmHg compared to supine, or drop in standing 
diastolic blood pressure >=10 mmHg compared to supine.
Treatment-emergent orthostatic hypotension means if at baseline subject did not have SBP 
drop>=20 and no DBP drop>=10 compared to supine, but developed one or more of these two
events during postbaseline visits.
Orthostatic tachycardia by numerical criteria is defined by the following numerical criteria:
Standing HR increases by >30 beats/min compared to supine AND absolute standing HR is 
>100 beats/min.
Orthostatic tachycardia without orthostatic hypotension will be considered a true orthostatic 
tachycardia and an instance of treatment emergent true orthostatic tachycardia is defined 
below:
1. Orthostatic tachycardia by above numerical criteria
2. No orthostatic hypotension (i.e. neither standing SBP drop by >20 nor standing DBP 
drop >10 compared to supine) at the same time point.
3. Does not meet criteria #1 and #2 at Baseline.
Additionally, instances of orthostatic hypotension by numerical criteria and treatment-
emergent orthostatic hypotension, and instances of orthostatic tachycardia by numerical 
criteria and treatment-emergent true orthostatic tachycardia will be summarized by treatment 
group and visit, overall and by stratification factors.
Listing of vital signs including orthostatic changes will be provided.
In addition, the number (percentage) of subjects with clinically notable vital signs will be 
summarized by treatment group. Table 6 presents the clinical notable ranges.
Table 6
Clinical Notable Ranges for Vital Signs
Vital Sign
Criterion for Low
Criterion for High


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Pulse (bpm)
< 50
> 100
Temperature (°C)
< 36
> 38
Weight (kg)
< 45
> 100
Systolic BP
< 90
> 160
Diastolic BP
< 60
> 100
5.6.5
Electrocardiograms
12-lead ECG will be performed at the baseline and post-baseline visit. The mean QTcF and 
other ECG intervals based on triplicate ECG will be obtained. Descriptive statistics for ECG 
parameters (QTcB, QTcF, PR interval QRS duration and RR interval) and changes from 
baseline will be presented by visit, treatment group, overall and by stratification factors.  
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; abnormal, clinically significant) to each post-baseline 
visit and to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in QTc Fridericia during the treatment period will be summarized according to the 
following categories.
Clinically borderline or abnormal ECG results QTc Fridericia will be categorized as follows:
Absolute QTcF interval prolongation:  
•
QTcF interval >450 msec
•
QTcF interval >480 msec
•
QTcF interval >500 msec
Change from baseline in QTcF interval:  
•
QTcF interval increases from baseline >30 msec
•
QTcF interval increases from baseline >60 msec
Plus at least one postbaseline QTcF interval >450 msec and increase from baseline >60 msec.


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The number (percentage) of subjects, by treatment group and stratification factor, with at 
least 1 post-baseline abnormal ECG results during the treatment period, Weeks 2, 4, 6, 9 and 
12 and EOT will be summarized according to the following categories:

QTcF prolongation by >60 ms from baseline and absolute QTcF >450 ms

QTcF prolongation to >500 ms

Change from baseline of PR >= 25% to an absolute PR value of > 220 msec

Change from baseline of QRS >= 25% to an absolute QRS value of > 120 msec.
5.6.6
Other Safety Analyses
5.6.6.1
C-SSRS
The C-SSRS responses will be mapped to C-CASA as suggested by the C-SSRS Columbia 
website http://www.cssrs.columbia.edu/clinical_trials.html.
Number (percentage) of subjects with any treatment-emergent suicidal ideation, suicidal 
behavior, and suicidality (suicidal ideation and/or behavior) will be displayed. “Treatment-
emergence” is used for any new or worsened events during randomization phase (treatment 
and follow-up) compared with the baseline C-SSRS assessment. This will be produced for at 
any point during the study, and by visit.
Shift from baseline to the maximum suicidal ideation severity rating (0=no ideation present 
to 5=active ideation with specific plan and intent) during randomization phase will assess 
worsening of suicidal ideation. Any score greater than 0 indicates the presence of suicidal 
ideation while a score of 4 (active suicidal ideation with some intent to act, without specific 
plan) or 5 (active suicidal ideation with specific plan and intent) can be used to indicate 
serious suicidal ideation.
5.6.6.2
UPDRS-III
Changes from baseline in the total score and four subscores of UPDRS-III will be summarized 
using descriptive statistics for continuous variable by visit and treatment group.
This scale evaluates extrapyramidal features in motor function in Parkinson’s disease. It 
contains 33 items in 18 categories:  (1) speech, (2) facial expression, (3) rigidity, (4) finger 
tapping, (5) hand movements, (6) supinational and pronation movements of hands, (7) toe 
tapping, (8) leg agility, (9) arising from chair, (10) gait, (11) freezing of gait, (12) postural 
stability, (13) posture, (14) body bradykinesia, (15) postural tremor of hands, (16) kinetic 
tremor of hands, (17) rest tremor  amplitude and (18) constancy of rest tremor.  Each item is 
scored 0 to 4, giving a total score range 0 to 132.  As far as is practical, the motor assessments 
should be made with the subject in the “on” state at each visit and at the same time relative to 
the subject’s last dose of Parkinson’s disease medication (such as L-dopa).  The four subscores 
are for tremor, rigidity, bradykinesia and postural instability and gait difficulty (PIGD), as 
calculated per Section 8.4.


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The above summary will be repeated where UPDRS and their subscores will be censored if 
there are changes in the subjects DLB motor medications, censoring will occur at the date of 
medication change, no imputations will be made.
5.7
Other Analyses
The following endpoints will be analyzed in the FAS using ANCOVA or GLMM as 
appropriate, with MI assuming MAR:
Change from baseline in the quality of life endpoints (total score and domain scores of 
DEMQOL and DEMQOL-Proxy, the EQ-5D and EQ-5D Proxy index scores, and EQ VAS 
scale) at 12 weeks of treatment
Percent change from baseline in CSF cGMP concentrations after 9 weeks of treatment.
The ANCOVA model will include corresponding baseline as a covariate, with treatment 
group and randomization stratification variables as factors.
Description of DEMQOL and DEMQOL-Proxy:
The DEMQOL is a 28-item scale and DEMQOL-Proxy is a 31-item scale.  All items are given 
a score from 1 to 4 (1 = a lot, 2 = quite a bit, 3 = a little, and 4 = not at all) and summed to 
produce total score and domain scores (daily activities, memory, negative emotion and positive 
emotion). However, large score indicates improvement for some items and deterioration for 
other items. In order to produce total score and domain scores such that a large score indicates 
improvement, the item score assuming large is deteriorating has to be reversed using the 
formula: new item score = (5 – current item score) or missing if the current item score is 
missing. The item score needs to be reversed for the following items:
DEMQOL:  item1, item3, item5, item6, and item10;
DEMQOL-Proxy: item1, item4, item6, item8, and item11.
The missing item score will be imputed using developer’s algorithm as described in 
developer’s SPSS syntax (Appendix 13.2), i.e., if the number of missing item score for any 
subject is less than 15, then any missing item score will be imputed by subject’s mean item 
score based on non-missing items; otherwise, the missing item score is still missing and the 
corresponding domain score and overall score is missing. 
The responses for general quality of life item (very good, good, fair and poor) within 
DEMQOL and DEMQOL-Proxy are unscored and will be analyzed as ordinal response using 
GLMM. 
Description of EuroQol 5 Dimensions (EQ-5D):


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The EQ-5D-5L and Proxy version 1 for proxy EQ 5D-5L will be utilized in this study.  The 
EQ-5D-5L scale consists of 5 specific questions (regarding mobility [walking], self-care 
[washing and dressing], usual activities, pain/discomfort, and anxiety/depression) with 5 levels 
of responses to each of the 5 questions and 1 overall health rating (EQ VAS).  EQ-5D-5L health 
states, defined by the EQ-5D-5L descriptive system (responses and questions), will be 
converted into a single index value (or utility score) using conversion matrix from the 
developer based on country specific value sets, which is stored in the excel file EQ-5D-
5L_Crosswalk_Index_Value_Calculator and demonstrated by SAS syntax based on United 
States (Appendix 13.3). The index values, presented in country specific value sets, are a major 
feature of the EQ-5D instrument, facilitating the calculation of quality-adjusted life years 
(QALYs) that are used to inform economic evaluations of health care interventions. The EQ 
VAS scale is numbered from 0 (the worst health) to 100 (the best health).
5.8
Exploratory Analyses
Exploratory analyses may be conducted as appropriate. Any exploratory analyses that are
performed will be appropriately titled/labeled as exploratory and will be clearly distinguished
from planned analyses when results are reported in the Clinical Study Report.
6
INTERIM ANALYSES
This is a fixed design.  There is no interim analysis of efficacy and no alpha spending before 
final analysis.  
7
CHANGES IN THE PLANNED ANALYSES
Due to correspondence with the FDA during the study, the primary analyses for the non-
EMA registrations were changed during the study to use MMRM for continuous efficacy 
data and GLMM for categorical efficacy data.   The pre-planned analyses were kept for EMA 
registration, based on pre-study scientific advice from the EMA.  The overall change was the 
ordering of importance of these analyses for each specific registration.
The co-primary analyses of MoCA and CIBIC-Plus will not be censored based on changes in 
the AChEI and non-AChEI restricted medications.  This is based on review of blinded data 
which showed no improvement on efficacy after the use of this medication.  As a sensitivity 
analysis, changes in AChEI restricted medications will be censored for MoCA and changes 
in either AChEI or non-AChEI restricted medications will be censored for CIBIC-Plus. The 
censoring differs based on the clinical interpretation that CIBIC-Plus measures aspects that 
could change with changes in the non-AChEI restricted medications.  


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8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
Efficacy data handling 
8.1.1
Pre-randomization/Baseline Efficacy
Baseline for all efficacy endpoints is defined as the last pre-treatment assessment. Additional 
baseline or mean baseline based on the mean of all pre-randomization values at the Screening 
and Baseline assessment will be explored to assess the potential pre-randomization 
variability in MoCA.  
8.1.2
Treatment Duration for Efficacy Analyses 
If additional data are collected other than scheduled visits, the additional data will be mapped 
to the closest scheduled visit if the data on this scheduled visit is missing. 
A treatment visit is defined as occurring between the first dose and Early Discontinuation 
(ED) Visit (for early discontinuations) or Week 12 visit (for completers). A Post ED visit is 
defined as occurring after the ED Visit, more detail below.
To allow for the separate analyses where 1) all data is used and 2) only data up to and 
including ED visit is used, two analysis flags will be presented for efficacy analysis visits.  
Subjects who have a post ED visit and treatment visit in the same window will flag 1) the one 
closest to target date out of the two visits for all data, or 2) the treatment visit for data up to 
ED visit.
Table 7
Mapping of Study Day Ranges to Week for Efficacy
Windowing Period
Study Day Range 
(Relative to First Dose)
Week
Screening
(-42) Day (-8)
Baseline
(-7) Day (-1)
Analysis Baseline
-
a
Treatment
1 Day 63
6 (d)
Treatment
64 Day 98
12 (d)
Post ED
1 Day 63
6 (e)
Post ED
64 Day 98
12 (e)
End of Treatment (EOT)
-
b
Follow up
Follow up visit
c


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a:  All pretreatment assessments are conducted during Screening/Baseline Periods before 
Day 1. The Analysis Baseline is the last non-missing value measured during pretreatment 
phase.
b:  For completer, EOT is the Week 12 visit. For early discontinuation, EOT is the Early 
Discontinuation (ED) visit. If the above visits are missing, then the last non-missing value 
collected not later than 7 days after the last dose will be used.
c:  If follow up visit is missing, there will be no imputed follow up visit.  Unscheduled visits 
can be mapped to follow up for listings, but the CRF follow up visit will be used for analysis.
d: For assessments with no Week 6 planned assessment, the window for the Week 12 
assessment is 1 ≤Day ≤ 98. The data must be within in the date of first dose and date of ED 
visit (for early discontinuation subjects). For completers, date of last dose is irrelevant, 
window the visit based on study day range in above table.
e: These subjects have been discontinued from treatment but continue the study untreated. 
They will be flagged as Post ED in the data listings and datasets. These Post ED visits must 
be after the early discontinuation visit date. For assessments with no Week 6 planned 
assessment, the window for the Week 12 assessment is 1 ≤ Day ≤ 98.  For the analysis flag 
based on all data, where subjects have both Week 6 and Week 6 Post ED, the visit closest to 
the target date will be used, the same is true for Week 12.
8.1.3
Efficacy Data Collected After the ED Visit 
Subjects who discontinue study drug are expected to continue in the study for the originally
scheduled visits, starting with next such visit that is after the Early Discontinuation (ED)
Visit. The scheduled visits post ED will be flagged to reflect its post ED status. The summary 
statistics by visit will presented twice, 1) for all data including those post ED, and 2) for data 
up to and including the ED visit.
8.1.4
Censoring of Efficacy Data Based on Changes in Medications
There are two types of censoring as part of the sensitivity analyses of the co-primary 
endpoints, censoring data based on changes to AChEI medications and censoring data based 
on changes in both AChEI and non-AChEI restricted medications.  
MoCA AChEI only. CIBIC-Plus AChEI and non-AChEI restricted medications are censored.  
This is due to the type of effects measured by each set of scales and how the effects of 
changes in the groups of medications may affect these.


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8.2
Safety data handling 
8.2.1
Baseline Safety 
The baseline value for all safety endpoints will be the last non-missing measurement 
occurring prior to the first dose of the study medication.
8.2.2
Treatment Duration for Safety Analyses 
The treatment duration for all safety variables is considered to begin on Day 1 and ends 28 
days after the last dose of study medication. Treatment emergent safety data (ie labs, vital 
signs and ECGs) are defined as observations that were recorded during treatment or within 
28 days following the last dose of study drug, these will be flagged in the listings as “off 
treatment, but treatment emergent”. This data will be windowed and summarized as 
described below. Data after 28 days of last dose will be flagged as Post TE and listed only.
For summaries of safety by time points, the time points will be relative to date of first dose.  
For standardized reporting, study day windows relative to the first dose (Day 1) in the study 
will be applied to determine into which week the data will be mapped.  All pretreatment 
assessments are conducted during Screening/Baseline Periods before Day 1. The Analysis 
Baseline is the last non-missing pretreatment assessments. Scheduled, unscheduled, and early 
discontinuation visits will be mapped to weeks.  Table 8 below gives the mapping of relative 
day ranges to week for non-AE safety variables. If a subject did not have a recorded 
observation falling within a given range of days in order to be assigned to a week, the 
subject’s data for that week will be regarded as missing for summarization purposes.  If there 
are two or more assessments in the same window, the following rules will be used:
•
If the window is for the screening/baseline assessment, then the latest assessment will be 
used in the summary tables;
•
If the window is for the follow-up assessment, then the latest assessment will be used in 
the summary tables;
•
If the window is not for the screening/baseline or the follow-up assessment, then the 
assessment closest to the scheduled assessment will be used in the summary tables.  Note 
that if two assessments are equidistant from the scheduled assessment then the last 
assessment of the two (within the allowable window) will be used.
Table 8
Mapping of Study Day Ranges to Week for Safety
Windowing Period
Study Day Range 
(Relative to First Dose)
Week
Screening
(-42) Day (-8)
Baseline
(-7) Day (-1)


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Analysis Baseline
-
a
Treatment
1 Day 21
2
Treatment
22 Day 35
4
Treatment
36 Day 53
6
Treatment
54 Day 74
9
Treatment
75 Day 98
12
End of Treatment (EOT)
-
b
Follow up
Follow up visit
c
a:  All pretreatment assessments are conducted during Screening/Baseline Periods before 
Day 1. The Analysis Baseline is the last non-missing value measured during pretreatment 
phase.
b:  For completer, EOT is the Week 12 visit. For early discontinuation, EOT is the Early 
Discontinuation (ED) visit. If the above visits are missing, then the last non-missing value 
collected not later than 7 days after the last dose will be used.
c:  If follow up visit is missing, there will be no imputed follow up visit.  
For subject visits after the treatment emergent period (not defined as a CRF follow up visit) 
will be labelled as Post TE and listed only.  
8.2.3
Handling of Replicate Data
A subject having an AE coded to the same preferred term more than once during the study will 
be counted only once in the incidence calculations for that AE. Similarly, if a subject has more 
than one AE in a single body system, the incidence will be counted only once for that body 
system. If a subject has the same AE more than once, the occurrence that is of greatest severity 
will be used in the calculation of the incidence of individual AE by severity. Similarly, the AE 
considered most closely related to study drug will be used in the calculation of incidence of 
individual AE by relationship in case a subject has the same AE more than once.
For the laboratory, vital signs, ECG, EEG and other safety variables datasets, the measurement 
noted as the scheduled visit measurement will be used in the analysis. If more than one 
assessment is present at a scheduled visit, then the nearest assessment for evaluation visit (day)
will be used in the summaries of the actual values and changes from baseline. In the event of 
two assessments being equally close to the scheduled visit (day), the last assessment will be 
used.
Handling of prior/concomitant medication 
If the subject has taken the same concomitant medication (as coded to preferred WHO-drug 
term) more than once, the subject will be counted only once in the tabulation.


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8.2.4
Safety Data Collected After the ED Visit 
No post TE data (data collected beyond treatment emergent window) will be summarized 
separately for safety summaries.  If data is within the treatment emergent period, they will be 
windowed into the visits as above. Data that is not treatment emergent will be flagged in the 
listings.
8.3
Algorithms for Efficacy Parameters 
This section describes the algorithms and missing data handling procedure to derive the totals 
scores for the efficacy parameters MoCA, NPI, MMSE, CFI, and SCOPA-Sleep.
Montreal Cognitive Assessment (MoCA)
This scale assesses different cognitive domains: attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, 
and orientation. It is reported to be useful to characterize global cognitive impairment in 
DLB. The MoCA scale is composed of 11 assessments. The following are the assessments 
and possible points earned for each assessment:
Visuoconstructional skills (0 – 5 points), Naming (0 – 3 points), Memory (No points), 
Attention: Forward/backward digit span (0 – 2 points), Attention: Vigilance (0 – 1 point), 
Attention: Serial 7s (0 - 3 points), Language: Sentence repetition (0 – 2 points), Language: 
Verbal fluency (0 – 1 points), Abstraction (0 – 2 points), Delayed recall (0 – 5 points), and 
Orientation (0 – 6 points).
The MoCA Total Score (range 0 to 30) = sum of all points earned. If any assessment is 
missing then the Total Score is missing. The lower the total score, the worse the cognitive 
impairment. 
Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus)
This scale is designed to measure various domains that describe subject function: general, 
mental/cognitive state, behavior, and activities of daily living. The CIBIC-Plus scores will 
be assigned by clinicians and the possible scores are: 1 (marked improvement), 2 (moderate
improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 6 (moderate 
worsening) and 7 (marked worsening).
Neuropsychiatric Inventory (NPI)
This scale assesses frequency and severity of 12 neuropsychiatric symptoms commonly 
described in dementia patients: delusions, hallucinations, agitation/aggression, 
depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, 
irritability/lability, motor disturbance, nighttime behaviors and appetite/eating changes. The 
scale is composed of 12 items, each item score ranges from 0 to 12. 


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The NPI Total Score (range 0 to 144) = sum of all item scores. If any item score is missing 
then the Total Score is missing. The higher the total score, the more severe the symptoms. 
A subscore covering the domains of delusions, hallucinations, apathy and depression (NPI-4) 
will also be derived. The subscore (0 to 48) = sum of 4 corresponding item scores.  If any one 
of the 4 item scores is missing then the subscore is missing.
The caregiver distress (NPI-D) is rated by caregiver based on his or her own stress on a five 
point scale from 0 - no distress, 1- minimal, 2 - mild, 3 - moderate, 4 - moderately severe, 5 -
very severe or extreme.
NPI-10 is the subscore (0-120) of all items except night-time behavior and appetite/eating 
changes. If any one of the 10 item scores are missing then the subscore is missing.
Mini-Mental State Examination (MMSE)  
The MMSE is composed of 30 questions group into domains, see Table 9.  For each of the 
MMSE domains add the correct responses.  If a domain has missing data then the domain is 
missing.  From the domains compute the six items as show in Table 9.  If any domain is missing 
then the item is missing.  The MMSE Total Score (range 0 to 30) = sum of the six items.  If 
any item score is missing then the Total Score is missing. The lower the total score, the worse 
the impairment.
Table 9
MMSE Domains and Items
Domain
Score 
Range
Item
Score 
Range
1. Orientation to Time
0 to 5
1. Orientation to Time
0 to 5
2. Orientation to Place
0 to 5
2. Orientation to Place
0 to 5
3. Registration
0 to 3
3. Registration
0 to 3
4. Attention and 
Calculationa
0 to 5
4. Attention and Calculation
0 to 5
5. Recall
0 to 3
5. Recall
0 to 3
6. Naming
0 to 2
6. Language (Sum of Naming, 
Repetition, Comprehension, 
Reading, Writing, and 
Drawing)
0 to 9


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7. Repetition
0 to 1
8. Comprehension
0 to 3
9. Reading
0 to 1
10. Writing
0 to 1
11. Drawing
0 to 1
Total Score
0 to 30
Cognitive Fluctuation Inventory (CFI)
This scale assesses cognitive fluctuation with the same format as the NPI. It evaluates 
fluctuation in various domains including attention, ability to performance daily functions, 
orientation, verbal communication and behaviour.  It is scored based on frequency and
severity with a score range of 0–12. The scale also assesses the degree of caregiver/informant 
distress engendered by the symptoms.
Scales for Outcome in Parkinson’s disease—Sleep (SCOPA-Sleep)
There are sections for night time and daytime sleep. There are 5 questions for night time 
sleep: (1) trouble falling asleep, (2) awakening during the night, (3) episodes lying awake too 
long at night, (4) early morning waking and (5) patient’s impression whether they had 
adequate duration of sleep at night. There are 6 questions for daytime sleep, (1) falling asleep 
unexpectedly during the day or evening, (2) falling asleep while sitting peacefully, (3) while 
watching television or reading, (4) while talking to someone, (5) trouble staying awake 
during the day or evening, and (6) experiencing falling asleep as a problem.
8.4
Algorithms for Safety Parameters 
UPDRS-III subscores are defined as follows:
Tremor: sum of MDS-UPDRS-III category 3.15 to 3.18 (sum of 10 items from 4 categories: 
3.15 Postural Tremor of the Hands, 3.16 Kinetic Tremor of the Hands, 3.17 Rest Tremor 
Amplitude, 3.18 Constancy of Rest Tremor).
Rigidity: sum of MDS-UPDRS-III category 3.3 (sum of 5 items from 1 category: 3.3 Rigidity).


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Bradykinesia: sum of category 3.4 to 3.8 and 3.14 (sum of 11 items from 6 categories: 3.4 
Finger Tapping, 3.5 Hand Movements, 3.6 Pronation-Supination Movements of Hands, 3.7 
Toe Tapping, 3.8 Leg Agility, 3.14 Global Spontaneity of Movement [Body Bradykinesia]).
Postural instability and gait difficulty (PIGD): sum of category 3.9 to 3.13 (sum of 5 items 
from 5 categories: 3.9 Arising from Chair, 3.10 Gait, 3.11 Freezing of Gait, 3.12 Postural 
Stability, 3.13 Posture).
DEMQOL subscores are defined as follows:
Daily activities contains items 20 to 28, memory contains items 14 to 19, negative emotion 
contains items 2, 4, 7, 8, 9, 11, 12 and 13 and positive emotion contains items 1, 3, 5, 6, and 
10.
DEMQOL-Proxy subscores are defined as follows:
Daily activities contains items 21 to 31, memory contains items 12 to 20, negative emotion 
contains items 2, 3, 5, 7, 9 and 10 and positive emotion contains items 1, 4, 6, 8, and 11.


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9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
10 STATISTICAL SOFTWARE
All statistical analyses will be performed by Eisai Inc., using SAS Version 9.4 or later.
11 MOCK TABLES, LISTINGS AND GRAPHS (TLGS)
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
1. Mehrotra D, Liu F. Permutt T. Missing data in clinical trials: control-based mean 
imputation and sensitivity analysis. Pharmaceutical Statistics. 2017; 16:378–392..
2. Yuan Y. Sensitivity Analysis in Multiple Imputation for Missing Data. SAS Global 
Forum 2014 Proceedings.  Paper SAS270-2014.


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13 APPENDICES
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results
The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, 
Appendix 2.
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109/L
<LLN –
3000/mm3
<3.0 –
2.0109/L
<3000 –
2000/mm3
<2.0 –
1.0109/L
<2000 –
1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN –
800/mm3
<LLN –
0.8109/L
<800 –
500/mm3
<0.8 –
0.5109/L
<500 –
200/mm3
<0.5 –
0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN –
1.5109/L
<LLN –
1500/mm3
<1.5 –
1.0109/L
<1500 –
1000/mm3
<1.0 –
0.5109/L
<1000 –
500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN –
75.0109/L
<LLN –
75,000/mm3
<75.0 –
50.0109/L
<75,000 –
50,000/mm3
<50.0 –
25.0109/L
<50,000 –
25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORA
TORY


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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ULN
>3.0 –
5.0ULN
>5.0 –
20.0ULN
>20.0ULN
ALT
>ULN –
3.0ULN
>3.0 –
5.0ULN
>5.0 –
20.0ULN
>20.0ULN
AST
>ULN –
3.0ULN
>3.0 –
5.0ULN
>5.0 –
20.0ULN
>20.0ULN
Bilirubin 
(hyperbilirubinemia)
>ULN –
1.5ULN 
>1.5 –
3.0ULN
>3.0 –
10.0ULN 
>10.0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
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ULN
>1.5 –
3.0ULN
>3.0 –
6.0ULN
>6.0ULN
GGT (γ-glutamyl 
transpeptidase) 
>ULN –
3.0ULN
>3.0 –
5.0ULN
>5.0 –
20.0ULN
>20.0ULN
Glucose, serum-high 
(hyperglycemia)
Fasting glucose 
value:
Fasting glucose 
value:
>250 – 500 
mg/dL;
>500 mg/dL;
>27.8 
mmol/L;


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
>ULN – 160 
mg/dL
>ULN – 8.9 
mmol/L 
>160 – 250 
mg/dL
>8.9 – 13.9 
mmol/L 
>13.9 – 27.8 
mmol/L;
hospitalization 
indicated
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
>300 –
500 mg/dL
>500 – 1000 
mg/dL
>1000 mg/dL
>11.4 mmol/L


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
1.71 – 3.42 
mmol/L
>3.42 –
5.7 mmol/L 
>5.7 – 11.4 
mmol/L
life-
threatening 
consequences 
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).


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13.2
SPSS Syntax Files for DEMQOL and DEMQOL-Proxy 
The SPSS syntax files present the developer’s algorithm to handle the missing item score in 
DEMQOL and DEMQOL-Proxy. 
APPENDIX 13.2.1
SPSS Syntax File for DEMQOL
***SPSS SYNTAX FILE FOR RECODING PWD DEMQOL DATA - JUNE 2005 ***
***DO NOT MODIFY***
*****
***RAW DATA SHOULD BE ENTERED AS FOLLOWS:
***A LOT = 1; QUITE A BIT = 2; A LITTLE = 3; NOT AT ALL = 4
*****
****
***CREATE A SEPARATE FILE FOR EACH TIME POINT (EG BASELINE, 6 
MONTHS AND 12
***MONTHS) AND CODE IT UP SEPARATELY.
***IF YOU WANT TO MERGE THE FILES TOGETHER AFTER CODING, SO AS TO 
LOOK AT
***CHANGE OVER TIME, YOU WILL NEED TO
***RENAME THE 6 MONTH AND 12 MONTH SCORES TO INDICATE WHICH TIME 
THEY ARE
***FROM (EG DEMTOT_S AND DEMTOT_T).
***BUT DO NOT DO THIS UNTIL YOU HAVE FULLY SCORED AND CODED THE 
DATA USING
***THE SYNTAX GIVEN HERE
*****
***CODING SYNTAX
************************************************************************


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***1. CHANGE VARIABLE NAMES SO THAT: QUESTION 1 = DEM1, QUESTION 2 = 
DEM2,
***QUESTION 3 = DEM3 ETC
***THEN CHECK THAT -99 IS SET AS THE MISSING VALUE
************************************************************************
***************************************************************************
**
***2. RECODE ALL THE POSITIVE ITEMS FOR DIRECTION, SO THAT
***FOR ALL ITEMS A HIGHER SCORE MEANS BETTER HRQL
***************************************************************************
***
***TO RECODE FOR DIRECTION ITEMS IN THE PATIENT DEMQOL***
RECODE dem1 dem3 dem5 dem6 dem10 dem29
(1=4) (2=3) (3=2) (4=1).
EXECUTE.
***************************************************************************
****
***3. IMPUTE MISSING DATA >=50% FOR ONLY THE 28 ITEMS THAT 
CONTRIBUTE TO
***THE SCORE
***IE EXCLUDING THE GLOBAL QUESTION (#29)
***************************************************************************
****
COMPUTE missall= NMISS (dem1, dem2, dem3, dem4, dem5, dem6, dem7, dem8, dem9,
dem10, dem11,
dem12, dem13, dem14, dem15, dem16, dem17, dem18, dem19, dem20, dem21, dem22,
dem23, dem24,


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dem25, dem26, dem27, dem28).
EXECUTE.
COMPUTE meanall = MEAN (dem1, dem2, dem3, dem4, dem5, dem6, dem7, dem8, dem9,
dem10, dem11,
dem12, dem13, dem14, dem15, dem16, dem17, dem18, dem19, dem20, dem21, dem22,
dem23, dem24,
dem25, dem26, dem27, dem28).
EXECUTE.
IF (MISSING (dem1) & missall < 15) dem1 = meanall .
EXECUTE .
IF (MISSING (dem2) & missall < 15) dem2 = meanall .
EXECUTE .
IF (MISSING (dem3) & missall < 15) dem3 = meanall .
EXECUTE .
IF (MISSING (dem4) & missall < 15) dem4 = meanall .
EXECUTE .
IF (MISSING (dem5) & missall < 15) dem5 = meanall .
EXECUTE .
IF (MISSING (dem6) & missall < 15) dem6 = meanall .
EXECUTE .
IF (MISSING (dem7) & missall < 15) dem7 = meanall .
EXECUTE .
IF (MISSING (dem8) & missall < 15) dem8 = meanall .
EXECUTE .


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IF (MISSING (dem9) & missall < 15) dem9 = meanall .
EXECUTE .
IF (MISSING (dem10) & missall < 15) dem10 = meanall .
EXECUTE .
IF (MISSING (dem11) & missall < 15) dem11 = meanall .
EXECUTE .
IF (MISSING (dem12) & missall < 15) dem12 = meanall .
EXECUTE .
IF (MISSING (dem13) & missall < 15) dem13 = meanall .
EXECUTE .
IF (MISSING (dem14) & missall < 15) dem14 = meanall .
EXECUTE .
IF (MISSING (dem15) & missall < 15) dem15 = meanall .
EXECUTE .
IF (MISSING (dem16) & missall < 15) dem16 = meanall .
EXECUTE .
IF (MISSING (dem17) & missall < 15) dem17 = meanall .
EXECUTE .
IF (MISSING (dem18) & missall < 15) dem18 = meanall .
EXECUTE .
IF (MISSING (dem19) & missall < 15) dem19 = meanall .
EXECUTE .
IF (MISSING (dem20) & missall < 15) dem20 = meanall .
EXECUTE .


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IF (MISSING (dem21) & missall < 15) dem21 = meanall .
EXECUTE .
IF (MISSING (dem22) & missall < 15) dem22 = meanall .
EXECUTE .
IF (MISSING (dem23) & missall < 15) dem23 = meanall .
EXECUTE .
IF (MISSING (dem24) & missall < 15) dem24 = meanall .
EXECUTE .
IF (MISSING (dem25) & missall < 15) dem25 = meanall .
EXECUTE .
IF (MISSING (dem26) & missall < 15) dem26 = meanall .
EXECUTE .
IF (MISSING (dem27) & missall < 15) dem27 = meanall .
EXECUTE .
IF (MISSING (dem28) & missall < 15) dem28 = meanall .
EXECUTE .
**********************************************
***4. TO COMPUTE OVERALL DEMQOL SCORE
***NOTE THAT THE SCORE CONSISTS OF ITEMS 1-28 ONLY.
***QUESTION 29 DOES NOT CONTRIBUTE TO THE SCORE
**********************************************
COMPUTE demtot = dem1+ dem2 +dem3 + dem4 + dem5 + dem6 +dem7 + dem8 + dem9 +
dem10 + dem11+
dem12 + dem13 + dem14 + dem15 + dem16 + dem17+ dem18 + dem19 + dem20 + dem21 +


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dem22 + dem23 + dem24 +
dem25 + dem26 + dem27 + dem28.
EXECUTE.
APPENDIX 13.2.2
SPSS Syntax File for DEMQOL-Proxy
***SPSS SYNTAX FILE FOR RECODING DEMQOL-PROXY DATA - JUNE 2005***
***DO NOT MODIFY***
*****
***RAW DATA SHOULD BE ENTERED AS FOLLOWS:
***A LOT = 1; QUITE A BIT = 2; A LITTLE = 3; NOT AT ALL = 4
*****
****
***CREATE A SEPARATE FILE FOR EACH TIME POINT (EG BASELINE, 6 
MONTHS AND 12
***MONTHS) AND CODE IT UP SEPARATELY.
***IF YOU WANT TO MERGE THE FILES TOGETHER AFTER CODING, SO AS TO 
LOOK AT
***CHANGE OVER TIME, YOU WILL NEED TO
***RENAME THE 6 MONTH AND 12 MONTH SCORES TO INDICATE WHICH TIME 
THEY ARE
***FROM (EG CDEMTOT_S AND CDEMTOT_T).
***BUT DO NOT DO THIS UNTIL YOU HAVE FULLY SCORED AND CODED THE 
DATA USING
***THE SYNTAX GIVEN HERE
*****
***CODING SYNTAX
************************************************************************


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***1. CHANGE VARIABLE NAMES SO THAT: QUESTION 1 = CDEM1, QUESTION 2 
= CDEM2,
***QUESTION 3 = CDEM3 ETC FOR CARER VERSION
***THEN CHECK THAT -99 IS SET AS THE MISSING VALUE
************************************************************************
***************************************************************************
**
***2. RECODE ALL THE POSITIVE ITEMS FOR DIRECTION, SO THAT
***FOR ALL ITEMS A HIGHER SCORE MEANS BETTER HRQL
***************************************************************************
***
***TO RECODE FOR DIRECTION OF ITEMS IN CARER DEMQOL***
RECODE cdem1 cdem4 cdem6 cdem8 cdem11 cdem32 (1=4) (2=3) (3=2) (4=1).
EXECUTE.
***************************************************************************
****
***3. TO IMPUTE MISSING DATA >=50% FOR ONLY THE 31 ITEMS IN MAIN 
INSTRUMENT,
***EXCLUDING THE GLOBAL QUESTION (#32)
***************************************************************************
****
COMPUTE missall = NMISS (cdem1, cdem2, cdem3, cdem4, cdem5, cdem6, cdem7, 
cdem8,
cdem9, cdem10, cdem11,
cdem12, cdem13, cdem14, cdem15, cdem16, cdem17, cdem18, cdem19, cdem20, cdem21,
cdem22, cdem23, cdem24,
cdem25, cdem26, cdem27, cdem28, cdem29, cdem30, cdem31).


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EXECUTE.
COMPUTE meanall = MEAN (cdem1, cdem2, cdem3, cdem4, cdem5, cdem6, cdem7, 
cdem8,
cdem9, cdem10, cdem11,
cdem12, cdem13, cdem14, cdem15, cdem16, cdem17, cdem18, cdem19, cdem20, cdem21,
cdem22, cdem23, cdem24,
cdem25, cdem26, cdem27, cdem28, cdem29, cdem30, cdem31).
EXECUTE.
IF (MISSING (cdem1) & missall < 16) cdem1 = meanall .
EXECUTE .
IF (MISSING (cdem2) & missall < 16) cdem2 = meanall .
EXECUTE .
IF (MISSING (cdem3) & missall < 16) cdem3 = meanall .
EXECUTE .
IF (MISSING (cdem4) & missall < 16) cdem4 = meanall .
EXECUTE .
IF (MISSING (cdem5) & missall < 16) cdem5 = meanall .
EXECUTE .
IF (MISSING (cdem6) & missall < 16) cdem6 = meanall .
EXECUTE .
IF (MISSING (cdem7) & missall < 16) cdem7 = meanall .
EXECUTE .
IF (MISSING (cdem8) & missall < 16) cdem8 = meanall .
EXECUTE .


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IF (MISSING (cdem9) & missall < 16) cdem9 = meanall .
EXECUTE .
IF (MISSING (cdem10) & missall < 16) cdem10 = meanall .
EXECUTE .
IF (MISSING (cdem11) & missall < 16) cdem11 = meanall .
EXECUTE .
IF (MISSING (cdem12) & missall < 16) cdem12 = meanall .
EXECUTE .
IF (MISSING (cdem13) & missall < 16) cdem13 = meanall .
EXECUTE .
IF (MISSING (cdem14) & missall < 16) cdem14 = meanall .
EXECUTE .
IF (MISSING (cdem15) & missall < 16) cdem15 = meanall .
EXECUTE .
IF (MISSING (cdem16) & missall < 16) cdem16 = meanall .
EXECUTE .
IF (MISSING (cdem17) & missall < 16) cdem17 = meanall .
EXECUTE .
IF (MISSING (cdem18) & missall < 16) cdem18 = meanall .
EXECUTE .
IF (MISSING (cdem19) & missall < 16) cdem19 = meanall .
EXECUTE .
IF (MISSING (cdem20) & missall < 16) cdem20 = meanall .
EXECUTE .


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IF (MISSING (cdem21) & missall < 16) cdem21 = meanall .
EXECUTE .
IF (MISSING (cdem22) & missall < 16) cdem22 = meanall .
EXECUTE .
IF (MISSING (cdem23) & missall < 16) cdem23 = meanall .
EXECUTE .
IF (MISSING (cdem24) & missall < 16) cdem24 = meanall .
EXECUTE .
IF (MISSING (cdem25) & missall < 16) cdem25 = meanall .
EXECUTE .
IF (MISSING (cdem26) & missall < 16) cdem26 = meanall .
EXECUTE .
IF (MISSING (cdem27) & missall < 16) cdem27 = meanall .
EXECUTE .
IF (MISSING (cdem28) & missall < 16) cdem28 = meanall .
EXECUTE .
IF (MISSING (cdem29) & missall < 16) cdem29 = meanall .
EXECUTE .
IF (MISSING (cdem30) & missall < 16) cdem30 = meanall .
EXECUTE .
IF (MISSING (cdem31) & missall < 16) cdem31 = meanall .
EXECUTE .
****************************************************
***4. TO COMPUTE OVERALL DEMQOL -PROXY SCORE


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***NOTE THAT THE SCORE CONSISTS OF ITEMS 1-31 ONLY.
***QUESTION 32 DOES NOT CONTRIBUTE TO THE SCORE
****************************************************
COMPUTE cdemtot = cdem1 + cdem2 + cdem3 + cdem4 + cdem5 + cdem6 + cdem7+ 
cdem8 +
cdem9 + cdem10 + cdem11+
cdem12 + cdem13 + cdem14 + cdem15 + cdem16 + cdem17 + cdem18 + cdem19 + cdem20 
+
cdem21 + cdem22 + cdem23 + cdem24 +
cdem25 + cdem26 + cdem27+ cdem28 + cdem29 + cdem30 + cdem31.
EXECUTE.
13.3
EQ-5D-5L_Crosswalk_Index_Value_Calculator and SAS Syntax File for 
EQ-5D 
The excel file EQ-5D-5L_Crosswalk_Index_Value_Calculator.v2 includes a data matrix to 
represents the relationship between 5L profile and the single index value (or utility score) based 
on country specific value sets. The SAS syntax file, SAS syntax crosswalk values EQ-5D-5L 
Unit.docx, presents the developer’s algorithm to convert EQ-5D-5L health states into a single 
index value (or utility score) using the United States (US) value set. These documents are 
saved separately.


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13.4
Imputation of Missing Start and End Dates for AE and Concomitant 
Medication
Description of Incomplete AE End Date 
Imputed  date
YearMonth earlier than YearMonth of Date of Death
Impute to the last day of the month
YearMonth equals YearMonth of Date of Death
Date of Death
Year earlier than Year of Date of Death
Impute to the last day of the year
Year equals Year of Date of Death
Date of Death
Date of Death
YearMonth
Impute to the last day of the month
Year
Impute to the last day of the year
No imputation
Description of Incomplete AE Start Date 
Imputed  date
Day missing (YearMonth Only)
YearMonth earlier than YearMonth of First Dose Date
Impute to first of the month
YearMonth equal YearMonth of First Dose Date
Impute to First Dose Date or AE End Date, whichever is earlier
YearMonth greater than YearMonth of First Dose Date
Impute to first of the month
Month missing (Year) 
Year earlier than Year of First Dose Date
Impute to first of the year
Year equal Year of First Dose Date
Impute to First Dose Date or AE End Date, whichever is earlier
Year greater than Year of First Dose Date
Impute to first of the year
Impute to First Dose Date or AE End Date, whichever is earlier
Description of Incomplete AE Start Time 
Imputed  Time
Hour Missing (no Time present)
Impute to 0
Minutes Missing (hour only)
Impute to 0
note: seconds not imputed
Description of Incomplete AE Stop Time 
Imputed  Time
Hour Missing (no Time present)
Impute to 23
Minutes Missing (hour only)
Impute to 59
note: seconds not imputed
ALL is missing and Date of Death is missing 
ALL is missing
Adverse Event Start & End Date Imputation
Day missing (YearMonth only) and Date of Death is not missing 
Month missing (Year) and Date of Death is not missing 
ALL is missing and Date of Death is not missing 
Day missing (YearMonth) and Date of Death is missing 
Month missing (Year) and Date of Death is missing 


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There is clear evidence the drug was STOPPED BEFORE the Screening Visit (from Prior Meds page)
Description of Incomplete Med End Date 
Imputed  date
YearMonth earlier than YearMonth of Date of Screening Impute to the last day of the month
YearMonth equals YearMonth of Date of Screening
Date of Screening
Year earlier than Year of Date of Screening
Impute to the last day of the year
Year equals Year of Date of Screening
Date of Screening
Date of Screening
There is NO clear evidence the drug was STOPPED BEFORE the Screening Visit
Description of Incomplete Med End Date 
Imputed  date
YearMonth earlier than YearMonth of Date of Death
Impute to the last day of the month
YearMonth equals YearMonth of Date of Death
Date of Death
Year earlier than Year of Date of Death
Impute to the last day of the year
Year equals Year of Date of Death
Date of Death
Date of Death
YearMonth
Impute to the last day of the month
Year
Impute to the last day of the year
No imputation
Description of Incomplete Med Start Date Imputed  date
Day missing (YearMonth Only)
YearMonth earlier than YearMonth of First Dose Date
Impute to first of the month
YearMonth equal YearMonth of First Dose Date
Impute to First Dose Date or Med End Date, whichever is earlier
YearMonth greater than YearMonth of First Dose Date
Impute to first of the month
Month missing (Year) 
Year earlier than Year of First Dose Date
Impute to first of the year
Year equal Year of First Dose Date
Impute to First Dose Date or Med End Date, whichever is earlier
Year greater than Year of First Dose Date
Impute to first of the year
Impute to First Dose Date or Med End Date, whichever is earlier
ALL is missing
Medication Start & End Date Imputation
Day missing (YearMonth) and Date of Screening is not missing 
Month missing (Year) and Date of Screening is not missing 
ALL is missing and Date of Screening is not missing 
Day missing (YearMonth only) and Date of Death is not missing 
Month missing (Year) and Date of Death is not missing 
ALL is missing and Date of Death is not missing 
Day missing (YearMonth) and Date of Death is missing 
Month missing (Year) and Date of Death is missing 
ALL is missing and Date of Death is missing 


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E2027-G000-201_SAP_final_v4
Biostatistics Approval
14-Apr-2020 15:02 GMT-04
Biostatistics Approval
14-Apr-2020 15:05 GMT-04
Clinical Approval
14-Apr-2020 15:11 GMT-04
PPD