Conditions: Lewy Body Disease Parkinson Disease
Keywords: E2027 Amyloid Copathology Parkinson's Disease Dementia Dementia With Lewy Bodies
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The purpose of study is to demonstrate the pharmacodynamic (PD) effects of E2027 on cerebrospinal fluid (CSF) cyclic guanosine monophosphate (cGMP) in participants with DLB and PDD with and without amyloid copathology after 9 weeks of treatment.

Detailed description:

Arms:
arm 1: Participants with DLB (without amyloid copathology) will receive E2027 50 milligram (mg) capsules, orally, once daily up to 12 weeks. arm 2: Participants with DLB (with amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks. arm 3: Participants with PDD (without amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks. arm 4: Participants with PDD (with amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks.

Interventions: intervention 1: E2027
Intervention descriptions: intervention 1: Oral hypromellose capsules.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol  
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Page 1 of 102  
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E2027-A001-203 
Study Protocol 
Title: 
An Open-Label Study To Evaluate the Pharmacodynamic Effects, 
Efficacy, Safety, and Tolerability of E2027 in Subjects With 
Dementia With Lewy Bodies or Parkinson’s Disease Dementia 
With or Without Amyloid Copathology 
Sponsor: 
Eisai Inc. 
100 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
US 
 
 
Sponsor’s 
Investigational 
Product Name: 
E2027 
Indication: 
Dementia with Lewy bodies and Parkinson’s disease dementia 
Phase: 
2 
Approval Date:  
V1.0 
19 Nov 2020 (original protocol) 
IND Number: 
123614 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
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 (IUPAC) 
Study Protocol Title 
An Open-Label Study to Evaluate the Pharmacodynamic Effects, Efficacy, Safety, and Tolerability 
of E2027 in Subjects With Dementia With Lewy Bodies or Parkinson’s Disease Dementia With or 
Without Amyloid Copathology 
Sites 
Approximately 30 investigational sites in the United States (US) and Canada 
Study Period and Phase of Development 
Approximately 9 months for the study 
Phase 2 
Objectives 
Primary Objective 
• 
To demonstrate the pharmacodynamic (PD) effects of E2027 on cerebrospinal fluid (CSF) 
cyclic guanosine monophosphate (cGMP) in subjects with dementia with Lewy bodies (DLB) 
and Parkinson’s disease dementia (PDD) with and without amyloid copathology after 9 weeks 
of treatment 
Secondary Objective 
• 
To evaluate the safety and tolerability of E2027 in subjects with DLB and PDD  
Exploratory Objectives 
• 
To evaluate the efficacy of E2027 on the following endpoints after 12 weeks of treatment: 
- 
Montreal Cognitive Assessment (MoCA) 
- 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol Coding (WAIS-IV DSC) 
- 
Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) 
- 
Clinician Global Impression of Change (CGIC) 
- 
Cognitive Fluctuation Inventory (CFI) 
- 
Mini-Mental State Examination (MMSE) 
- 
Neuropsychiatric Inventory (NPI) 
- 
Scale for Assessment of Positive Symptoms in Parkinson’s Disease (SAPS-PD) 
- 
Functional Assessments Questionnaire (FAQ) 
• 
To explore the indirect PD effects of E2027 on plasma biomarkers and CSF biomarkers related 
to DLB and PDD 
• 
To explore the effects of E2027 on CSF cGMP, other plasma and CSF biomarkers, and clinical 
endpoints using other diagnostic subgroups classifications based on baseline biomarkers  
• 
To characterize the population pharmacokinetics (PK) of E2027 in subjects with DLB or PDD, 
including evaluation of the effects of intrinsic and extrinsic factors on the PK 


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• 
To explore the relationships amongst the PK exposure of E2027 in plasma/CSF and its effects 
on plasma/CSF biomarkers (including CSF cGMP) as well as clinical efficacy and safety 
endpoints  
• 
To explore the relationship amongst plasma and CSF biomarkers at baseline and after 
treatment with E2027  
• 
To collect genomic samples for exploratory investigation on heterogeneity in drug-response 
and clinical features of disease 
Study Design 
This is a multicenter, open-label study in subjects with DLB or PDD who will be treated with 
E2027 for 12 weeks.  Four subgroups of subjects will be enrolled as follows:  DLB without 
amyloid copathology, DLB with amyloid copathology, PDD without amyloid copathology, and 
PDD with amyloid copathology.  The presence of amyloid copathology is defined as ratio of 
plasma concentration of amyloid-β (Aβ)42/Aβ40 <0.092 (based on the C2N Preclivity assay).   
The study design allows for add-on therapy of E2027 to standard of care for DLB and PDD, which 
includes acetylcholinesterase inhibitor (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 to participate in this study but are not permitted to start such 
medications during the study.  It is required that in each subgroup there should be at least 1 subject 
who is not receiving AChEI or memantine during the study.  Subjects should be on stable doses of 
medications for the treatment of Parkinson’s disease, maintained without change during the study. 
For all subjects, study participation will comprise 2 Phases:  Pretreatment (Screening Period [up to 
6 weeks] and Baseline Period [up to 1 week]) and Treatment (Treatment Period [12 weeks] and 
Follow-up Period [4 weeks]).   
Pretreatment Phase 
Screening Period:  Screening will occur between Day -49 and Day -8.  The purpose of the 
Screening Period is to obtain informed consent and to establish protocol eligibility.  All subjects 
will be assessed for eligibility through review of medical history, physical examination (including 
neurological examination), laboratory tests, vital signs, and ECGs.   
Subjects with DLB 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.   
Subjects with PDD will be assessed on clinical scales of cognition and depression, safety MRI of 
the brain and DAT brain imaging or MIBG (if indicated in individual subjects and not previously 
performed) to support their diagnosis of Parkinson’s disease (and not other extrapyramidal or 
cerebrovascular diseases).   
Eligibility assessments at Screening will be conducted in 6 tiers, and subjects will need to satisfy 
eligibility criteria in each tier before proceeding to the next tier.   
The scores of various clinical scales (including NPI, Short Fluctuation Questionnaire [SFQ], CFI, 
and Unified Parkinson’s Disease Rating Scale Part III:  Motor Examination [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 or PDD 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.   


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All subjects who have completed screening assessments and are deemed eligible for the study will 
have a baseline CSF sample collected by lumbar puncture (LP).  The CSF sample will be collected 
in the morning, either in the fasted state or at least 2 hours after breakfast.  In subjects who require 
DAT or MIBG scan, the CSF collection should be at least 1 week after the scan. 
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 clinical assessments on cognition and depression) and at least 1 week after CSF 
collection.  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, followed by the WAIS-IV DSC and then the Clinician Interview Based 
Impression of Severity Plus Caregiver Input (CIBIS-Plus).  The caregiver or informant will also 
complete the CIBIS-Plus, NPI, CFI, SAPS-PD, and FAQ.  The rater administering the CIBIS-Plus 
should be independent of the rater(s) who administer the other clinical scales.   
At the Baseline Visit subjects will be assessed regarding other medical conditions and concomitant 
medications (including medications for DLB or PDD) 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 assessments including vital signs, ECGs, laboratory tests, and Columbia Suicide 
Severity Rating Scale (C-SSRS) will also be conducted.   
Treatment Phase 
Treatment Period:  After completing study assessments at the Baseline Visit, subjects who 
continue to be eligible will proceed to the Treatment Period on E2027 (50 mg once daily [QD]).  
They will be provided with 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 3, 6, 9, and 12 weeks on E2027.  Efficacy assessments will be performed after 
6 and 12 weeks on E2027 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 
efficacy assessment to be administered, followed by the WAIS-IV DSC (after 12 weeks only), then 
the CIBIC-Plus and finally the MMSE (after 12 weeks only).  Whenever possible, a subject should 
have the same rater administering the MoCA and the CIBIC-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 caregiver or informant will also complete the CIBIC-Plus, 
NPI, CFI, SAPS-PD (after 12 weeks only) and FAQ (after 12 weeks only).  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  and 12 weeks on study drug and formulate the CGIC of the 
subject’s clinical status from baseline.   
After subjects have completed 9 weeks of treatment with E2027 will have a 2nd CSF sample 
collected.  The CSF sample will be collected in the morning at approximately the same time as at 
Screening, either in the fasted state or at least 2 hours after breakfast.  A 2nd plasma sample for 
biomarkers will also be collected. 
Follow-Up Period:  After the Treatment Period, subjects will complete a Follow-Up Visit 4 weeks 
after the final dose of study drug.  Safety assessments will 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 


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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.  At these originally scheduled visits that take place after the ED Visit, blood PK samples, 
plasma biomarker samples, and CSF samples will not be collected.  
Conduct of the Study During the COVID-19 Pandemic and Other Extenuating Circumstances 
All study assessment and visit information affected by any extenuating circumstances (eg, the 
COVID-19 pandemic) will be collected on the electronic case report forms (eCRFs).  These 
include but are not limited to any visits or assessments that are missed or not done, any 
assessments that are performed remotely/offsite or in person/onsite, and any home delivery of 
investigational product. 
During the COVID-19 pandemic, and under other extenuating circumstances: 
• 
An extension of the Screening Period from 6 weeks to up to 10 weeks is allowed with sponsor 
approval on a subject by subject basis. 
• 
If subjects cannot visit the study site, all procedures which require physical contact with the 
subjects (eg, vital signs, ECGs, blood tests, physical examination, UPDRS-III) may be 
conducted via home visit (if feasible) with sponsor approval.  The brain or cardiac imaging 
during the Screening Visit must be conducted at the study site.  The CSF collection at the 
Screening Visit and Visit 6 (Week 9) must be conducted at the study site.  Other study 
procedures including all the efficacy endpoints, AEs, and concomitant medications review may 
be conducted remotely via telephone, sponsor approved telehealth, or home visit.  If it is not 
possible for subjects to attend the study site for the CSF collection Visit 6 (Week 9), this can be 
performed at an Unscheduled Visit as soon as possible after Week 9.  Study drug may be 
delivered to subjects’ homes if it is not possible to visit the study site to collect the study drug.   
Number of Subjects 
Approximately 64 subjects will be screened to provide a maximum of 32 treated subjects, with 
8 subjects in each of the 4 subgroups (DLB without amyloid copathology, DLB with amyloid 
copathology, PDD without amyloid copathology, and PDD with amyloid copathology).  Allowing 
for a 25% dropout rate there will be 24 treated subjects completing the study treatment, with 
6 subjects in each subgroup.  Further subjects may be screened and treated with E2027 if there are 
less than 6 completers in any of the subgroups. 
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) or meet 
criteria for probable PDD (as defined by the task force of the Movement Disorder Society).  
Specific situations regarding the use of imaging are described below: 
a. 
DLB subjects who have 1 core clinical feature only by the investigator and who do 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. 
DLB subjects who 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 do 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. 
DLB subjects who have 2 or more core clinical features by the investigator and the central 
reviewer and who do 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 


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sponsor medical monitor if the investigator considers that imaging is necessary to confirm 
the diagnosis. 
d. 
PDD subjects with clinical features that are consistent with the diagnostic criteria of 
probable PDD but in whom the investigator considers that there may be other diagnoses, 
DAT brain imaging scan or MIBG scan may be conducted after discussion with the 
sponsor medical monitor. 
3. MMSE >14 and <26 at Screening Visit 
4. For DLB subjects, have experienced visual hallucinations since onset of their DLB   
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.   
7. If receiving Parkinson’s disease medications, must have been on a stable dose for at least 
4 weeks before Screening Visit, with no plans for dose adjustment during the study. 
8. 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.  
9. 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. 
Exclusion Criteria 
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond those caused by the subject’s DLB or PDD, including any comorbidities detected by 
clinical assessment or MRI (identification of amyloid copathology is not exclusionary) 
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 and Yahr Scale (HYS) stage IV or higher 


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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  
6. Geriatric Depression Scale (GDS) score >8 
7. Severe visual or hearing impairment that may interfere with the subject study assessments 
including cognitive testing 
8. The following exclusions apply in relation to CSF sampling by LP:   
• 
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, obesity to the extent that it makes LP technically 
difficult, or inability to cooperate with LP due to cognitive impairment or motor 
symptoms) 
9. History of deep brain stimulation or other neurosurgical procedure for Parkinson’s disease 
10. Has 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. 
11. 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).  Low levels of vitamin B12 may be confirmed with reflex 
testing to include methylmalonic acid (MMA) analysis, (if available in region) and excluded 
only if MMA levels are also >ULN. 
12. 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 
13. Evidence of other clinically significant lesions that suggest a dementia diagnosis other than 
DLB or PDD 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 and 
will be read by an approved centralized reader. 
14. 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) 
15. Hypersensitivity to E2027 or any of the excipients   
16. 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)   
17. 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 


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18. 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:   
a. Physical examination, ECG, vital signs at Screening or Baseline Visit 
b. Laboratory tests at Screening Visit 
19. 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.   
20. 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   
21. 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. 
22. 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 
23. Taking any of the prohibited medications or not meeting the requirements regarding stable 
doses of permitted medications 
24. Participation in a clinical study involving any investigational drug/device for DLB or PDD 
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 
25. 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. 
26. Males who have not had a successful vasectomy (confirmed azoospermia) if their female 
partners are of childbearing potential and are not willing to use a highly effective contraceptive 
method throughout the study period and for 98 days after study drug discontinuation.  No 
sperm donation is allowed during the study period and for 98 days after study drug 
discontinuation. 
27. 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. 
28. Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following: 
- 
total abstinence (if it is their preferred and usual lifestyle) 
- 
an intrauterine device or intrauterine hormone-releasing system  


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- 
a contraceptive implant 
- 
an oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on the 
same dose of oral contraceptive throughout the study and for 28 days after study drug 
discontinuation.) 
- 
have a vasectomized partner with confirmed azoospermia 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation 
(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].) 
Study Treatment 
E2027 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.   
All subjects will take 2 × E2027 25 mg capsules.   
Comparator Drug:  Not applicable 
Duration of Treatment 
The total duration of study participation of each subject is approximately 23 weeks: 
• 
Up to 6 weeks for Screening Period 
• 
Up to 1 week for Baseline Period 
• 
Treatment Period of 12 weeks 
• 
Follow-up Period of 4 weeks 
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), 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 msec 
(Exclusion Criterion 16).   


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• 
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  
• 
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 of treatment with E2027   
The following restrictions apply to AChEIs (including donepezil, rivastigmine, galantamine) or 
memantine for treatment of DLB or PDD: 
• 
If a subject is already receiving AChEI or 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 AChEI or memantine at Screening, then these should not 
have been used at least 12 weeks before Screening and AChEI or memantine should not be 
started during the study until the Follow-Up Visit. 
• 
Subjects who start AChEI/memantine or change their dose of AChEI/memantine during the 
study should undertake an Unscheduled Visit before making such changes in their 
AChEI/memantine medications to undertake efficacy assessments (MoCA, CIBIC-Plus, NPI, 
CFI, CGIC) (unless they have been conducted within past 4 weeks).  This change in 
AChEI/memantine medications is considered a protocol deviation; the handling of efficacy 
data collected after the change of these medications in the efficacy analyses is described in the 
Statistical Analysis Plan (SAP).  
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 in the SAP.   
The following restrictions apply to medications for antipsychotic or neuroleptic drugs, 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. 


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• 
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, NPI, CFI, CGIC) (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 the SAP.   
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 
should 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 
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 or PDD.  The total 
possible score is 30 points; a score of 26 or above is considered normal.   
WAIS-IV DSC 
This is the Digit-Symbol Substitution Test from the WAIS-IV.  The test consists of small blank 
squares presented in rows with one of 9 numbers (1-9) randomly printed directly above each blank 
square.  A “key” is printed above the rows of blank squares.  The “key” pairs numbers 1 through 9 
with an unfamiliar symbol.  Following a short series of practice trials, the subject must use the key 
to fill in the blank squares in order (working from left to right across the rows) with the symbol that 
is paired with the number over the blank square.  The subject must work as fast as possible for 
120 seconds.  The measure of interest is known as the Digit Symbol Coding, which is the number 
of squares filled in correctly within the time limit (maximum score=135).  This test engages 
multiple cognitive abilities including attention, psychomotor speed, complex scanning, visual 
tracking, and immediate memory.  Alternate versions will include the identical symbols and digits 
re-paired. 
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 postbaseline as part of the given protocol. 
At the 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 the Treatment Period, 
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 


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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 (NPI-D).  It is rated from 0 to 144 with 
high scores meaning a greater neuropsychiatric disturbance.  Two subscores will be derived NPI-10 
(covering the domains of delusions, hallucinations, agitation/aggression, depression/dysphoria, 
anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability and motor 
disturbance) and NPI-4 (covering the domains of delusions, hallucinations, apathy, and 
depression).   
SAPS-PD 
The SAPS-PD is a structured clinical interview originally designed for use in schizophrenia. It 
includes 5 domains of positive symptoms:  hallucinations, delusions, bizarre behavior, positive 
formal thought disorder and inappropriate affect. The SAPS-PD is adapted from the Scale for 
Assessment of Positive Symptoms (SAPS) and includes items that are reflective of the 
hallucinations and delusions in PDD. It is a 9-item scale adapted from the hallucinations and 
delusions domains of the SAPS. There are 5 items for hallucinations (including auditory, voices 
conversing, somatic/tactile, visual and global hallucinations) and 4 items for delusions (including 
persecutory, jealousy, reference and global delusions).  Each item is scored on a scale of 0 to 5, 
with 0 being none and 5 representing severe and frequent symptoms.  Therefore, the SAPS-PD 
total score can range from 0 to 45 with higher scores reflecting greater severity of illness.  
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 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. 
CGIC 
The CGIC 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, behavior and 
the impact of the symptoms on the patient’s ability to function) and safety data. 
FAQ 
On the basis of interviews with the caregivers/informants, subjects will be rated for ability to carry 
out ten complex activities of daily living:  (1) manage finances, (2) complete forms, (3) shop, (4) 
perform games of skill or hobbies, (5) prepare hot beverages, (6) prepare balanced meal, (7) follow 
current events, (8) attend to television programs, books, and magazines, (9) remember 
appointments, and (10) travel out of the neighborhood.  Each activity will be rated as 0 (normal, 
does without difficulty), 1 (has difficulty but does by self), 2 (requires assistance), or 3 


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(dependent).  Scores will be summed across items to provide a total disability score (higher scores 
= greater impairment; maximum score = 30).  If an activity was never or very rarely performed 
premorbidly, it will be marked as “Not Applicable” and will not be included in the score.  A 
proportional score will be derived for subjects who mark any activity as ‘Not Applicable’ as 
follows (achieved score/(30 – 3 times the number of activities marked ‘Not Applicable’).   
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 Weeks 6, 9, and 12:  at predose (within 
30 minutes before dosing) and 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 eCRFs.   
CSF samples 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.  Another PK sample will be collected at 1 to 4 hours 
postdose. 
Baseline Biomarker Assessments 
A plasma sample will be collected during the Screening Period (Tier 3) to measure biomarkers 
related to Alzheimer’s disease (AD) copathology (including amyloid and p-tau) and other 
biomarkers related to DLB or PDD.  These baseline plasma amyloid Aβ42/Aβ40 ratio will be used 
to classify subjects into the various categories (DLB without amyloid copathology, DLB with 
amyloid copathology, PDD without amyloid copathology and PDD with amyloid copathology).  
The baseline plasma and CSF biomarkers may also be used to define other subgroups 
classifications of subjects for subgroup analyses. 
A CSF sample will be collected during the Screening Period (at least 7 days before the Baseline 
Visit) to measure baseline CSF cGMP and biomarkers related to DLB or PDD. These DLB or PDD 
related biomarkers may be used to define other subgroups classifications of subjects for subgroup 
analyses. 
Pharmacodynamic Assessments 
CSF samples will be collected during the Screening Period (at least 7 days before the Baseline 
Visit) and after 9 weeks on E2027.  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 be collected after the predose blood draw for PK 
and plasma biomarker analysis at the study visit after 9 weeks on E2027.  The CSF samples will be 
assayed for cGMP and E2027.  Other CSF biomarkers related to DLB or PDD or E2027 PD effects 
may also be assayed, if appropriate.   
A predose plasma sample will be collected at the study visit after 9 weeks on E2027.  It will be 
assayed for plasma biomarkers related to DLB or PDD or E2027 PD effects on these biomarkers if 
appropriate. 
Pharmacogenomic Assessments 
Blood samples will be collected as specified in the Schedule of Procedures/Assessments where 
feasible and in accordance with local regulations.  Participation in pharmacogenomic (PGx) 
assessments is voluntary and subjects must provide a separate informed consent before blood 
collection for PGx assessments.  


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The PGx blood samples may be used to genotype common and rare genetic variants (including 
apolipoprotein E [ApoE] genotype).  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 or PDD. 
Safety Assessments 
Safety will be assessed by monitoring and recording all AEs, regular 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 3 weeks 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.  It is recommended that 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).  
Bioanalytical Methods 
Plasma concentrations of E2027 and its metabolite HP4 and CSF concentrations of E2027 will be 
measured using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay 
methods.  
Plasma concentrations of Aβ42 and Aβ40 will be measured by the validated immunoprecipitation 
LC-MS/MS C2N Preclivity plasma assay.  Plasma concentrations of p-tau 181, glial fibrillary 
acidic protein (GFAP), and neurofilament light (NFL) will be measured by Quanterix Simoa 
plasma assay.   
CSF concentrations of cGMP will be measured using a validated assay.  Other CSF biomarkers 
represented by Aβ42, Aβ40, tau, p-tau will be measured by Lumipulse platform and CSF NFL, 
neuregulin (NRG) will be measured by Simoa. 
Statistical Methods 
Primary Endpoint 
• 
Percentage change from baseline in CSF cGMP at 9 weeks of treatment.   
Secondary Endpoints 
• 
Safety and tolerability of E2027 as measured by the following: 
- 
Incidence of AEs including severe AEs, serious AEs, AEs resulting in discontinuation   
- 
Incidence of orthostatic hypotension and orthostatic tachycardia   
- 
Incidence of markedly abnormal laboratory values and shifts from baseline of laboratory 
values   


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- 
Incidence of abnormal ECG parameters and abnormal ECG findings   
- 
Incidence of suicidality based on C-SSRS   
- 
Changes from baseline in the total score of UPDRS-III  
Exploratory Endpoints  
• 
The following clinical efficacy endpoints at 12 weeks of treatment 
- 
Change from baseline in MoCA total score 
- 
Change from baseline in WAIS-IV DSC score 
- 
CIBIC-Plus scale 
- 
CGIC scale 
- 
Change from baseline in CFI score 
- 
Change from baseline in MMSE total score 
- 
Change from baseline in NPI total score, subscores and caregiver distress score 
- 
Change from baseline in SAPS-PD total score 
- 
Change from baseline in FAQ total score 
• 
Change from baseline in CSF cGMP at 9 weeks of treatment 
• 
Percentage change and change from baseline at 9 weeks of treatment in other biomarkers in 
CSF and/or plasma, including using other diagnostic subgroups classifications based on 
baseline biomarkers (if appropriate) 
• 
PK of E2027 in subjects with DLB or PDD, using population modelling 
• 
Relationships between E2027 in plasma/CSF and its effects on the following variables  using 
PK/PD modelling, if data permit: 
- 
Plasma/CSF PD biomarkers (including CSF cGMP),  
- 
Clinical efficacy (including MoCA, WAIS-IV DSC, CIBIC-Plus, NPI, MMSE, CFI, 
SAPS-PD, FAQ, and CGIC at 12 weeks of treatment),  
- 
Safety variables 
• 
Relationships of the plasma and CSF PD biomarkers compared to MoCA, WAIS-IV DSC, 
CIBIC-Plus, NPI, MMSE, CFI, SAPS-PD, FAQ, and CGIC at 12 weeks of treatment, if data 
permit 
• 
Relationships amongst plasma biomarkers and CSF biomarkers at baseline and after treatment 
(if appropriate)  
• 
Subgroup analyses based on genotype classification for CSF cGMP changes from baseline and 
clinical endpoints 
Analysis Sets 
• 
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 post baseline safety assessment 
• 
The Full Analysis Set (FAS) is the group of subjects who receive at least 1 dose of study drug 
and have baseline and at least 1 post baseline MoCA measurement 
• 
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1 PD 
parameter 
Efficacy Analyses 
The exploratory efficacy endpoints will be summarized based on the FAS, by subject subgroup 
(DLB without amyloid copathology, DLB with amyloid copathology, PDD without amyloid 
copathology, and PDD with amyloid copathology). 


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Pharmacokinetic, Pharmacodynamic and Pharmacogenomic Analyses 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for E2027 concentration listings and for summaries of E2027 
concentrations in plasma and CSF by dose and day.   
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 and 2 studies.  
As appropriate, the effect of covariates on the PK of E2027, such as baseline 
characteristics/demographics will be evaluated.  Derived exposure parameters such as steady state 
area under the concentration time curve or average concentration of E2027 and other derived 
parameters may be calculated from the final PK model using the individual posterior estimates of 
the PK parameters and dosing history.  The details will be described in the separately prepared 
analysis plan and its report, and the results will not be included in the clinical study report. 
Pharmacodynamic Analyses 
The PD Analysis Set will be used for the summaries and analyses of CSF and plasma PD 
biomarkers.  The percentage change from baseline in CSF cGMP at 9 weeks of treatment will be 
analyzed to compare different subject subgroups (DLB without amyloid copathology vs DLB with 
amyloid copathology, and PDD without amyloid copathology vs PDD with amyloid copathology). 
Analyses, comparing the different subgroups, of the percentage change from baseline in CSF 
cGMP will be performed using an analysis of covariance, where baseline CSF cGMP will be 
included as a covariate.  The least square (LS) means, LS mean subgroup differences and 95% CIs 
will be presented. 
The change from baseline in CSF cGMP at 9 weeks of treatment will also be analyzed.  Other CSF 
and plasma PD biomarkers may be analyzed similarly, if appropriate. 
The CSF and plasma PD biomarkers will be summarized by subject subgroups, as appropriate.  
Summaries and figures will be produced exploring the relationships between CSF and plasma PD 
biomarkers and the efficacy endpoints. 
Pharmacodynamic/Pharmacokinetic Analyses 
The correlation amongst plasma and CSF exposure to E2027 and the various efficacy and 
biomarker endpoints will be explored graphically.  The details will be described in the separately 
prepared analysis plan and its report, and the results will not be included in the clinical study 
report. 
Pharmacogenomic Analyses 
The percentage change in CSF cGMP at 9 weeks, change in CSF cGMP at 9 weeks and other CSF 
and plasma PD biomarkers will be summarized by ApoE4 status, using the PD Analysis Set.  Other 
PGx data will be summarized similarly.   
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 subgroup and overall.  
Interim Analyses 
No interim analysis will be conducted. 


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Sample Size Rationale 
Assuming the standard deviation of percentage change from baseline in CSF cGMP at Week 9 is 
60 , the sample size of 6 completers per group (for 8 enrolled subjects per arm, assuming a 25% 
dropout rate), will have approximately 80% power to detect the difference in change from baseline 
of CSF cGMP of 100% between the DLB without amyloid copathology subgroup and the DLB 
with amyloid copathology subgroup.  The analysis between the PDD without amyloid copathology 
subgroup and the PDD with amyloid copathology subgroup, also has approximately 80% power to 
detect the difference in change from baseline of CSF cGMP of 100% (same assumptions as above).  
These sample size calculations illustrate the possible differences that could be seen between 
subgroups.  However, without previous data on the differences between subgroups in CSF cGMP, 
these are for illustration only and it is not expected statistical significance will be reached with 
6 subjects per subgroup. 
The probability of observing a difference in percentage of CSF cGMP between 2 subgroups (DLB 
without amyloid copathology subgroup minus DLB with amyloid copathology subgroup, or PDD 
without amyloid copathology subgroup minus PDD with amyloid copathology subgroup) ≥30% 
depends on the true difference between the 2 groups.  If the true difference is 100%, there will be 
97.8% probability that the observed difference is ≥30%.  If the true difference is 60%, the 
probability is 80.7%.  If the true difference is 10%, there will be 28.2% probability that the 
observed difference is ≥30%. 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................18 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................23 
5 
ETHICS............................................................................................................................25 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................25 
5.2 
Ethical Conduct of the Study .................................................................................26 
5.3 
Subject Information and Informed Consent ...........................................................26 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................27 
7 
INTRODUCTION ...........................................................................................................27 
7.1 
Compound Overview .............................................................................................28 
7.1.1 
Current Therapeutic Options........................................................................28 
7.1.2 
Therapeutic Pathway ....................................................................................29 
7.2 
Clinical Experience ................................................................................................29 
7.3 
Study Rationale ......................................................................................................32 
8 
STUDY OBJECTIVES ....................................................................................................34 
8.1 
Primary Objective ..................................................................................................34 
8.2 
Secondary Objective ..............................................................................................34 
8.3 
Exploratory Objectives ..........................................................................................34 
9 
INVESTIGATIONAL PLAN ..........................................................................................35 
9.1 
Overall Study Design and Plan ..............................................................................35 
9.1.1 
Pretreatment Phase .......................................................................................36 
9.1.1.1 
Screening Period ..................................................................................36 
9.1.1.2 
Baseline Period ....................................................................................37 
9.1.2 
Treatment Phase ...........................................................................................38 
9.1.2.1 
Treatment Period ..................................................................................38 
9.1.2.2 
Follow-Up Period.................................................................................39 
9.1.3 
Conduct of the Study During the COVID-19 Pandemic and Other 
Extenuating Circumstances ..........................................................................39 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................39 
9.3 
Selection of Study Population ................................................................................41 
9.3.1 
Inclusion Criteria .........................................................................................41 
9.3.2 
Exclusion Criteria ........................................................................................43 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................45 
9.4 
Treatment ...............................................................................................................46 
9.4.1 
Treatment Administered ..............................................................................46 


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9.4.2 
Identity of Investigational Product(s) ..........................................................46 
9.4.2.1 
Chemical Name of E2027 ....................................................................46 
9.4.2.2 
Comparator Drug .................................................................................46 
9.4.2.3 
Labeling for Study Drug ......................................................................47 
9.4.2.4 
Storage Conditions ...............................................................................47 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................47 
9.4.4 
Selection of Doses in the Study ...................................................................47 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................47 
9.4.6 
Blinding........................................................................................................47 
9.4.7 
Prior and Concomitant Therapy ...................................................................48 
9.4.7.1 
Drug-Drug Interactions ........................................................................48 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs .....................................48 
9.4.8 
Treatment Compliance .................................................................................50 
9.4.9 
Drug Supplies and Accountability ...............................................................50 
9.5 
Study Assessments .................................................................................................52 
9.5.1 
Assessments .................................................................................................52 
9.5.1.1 
Screening Assessments ........................................................................52 
9.5.1.1.1 
Demography ...................................................................................52 
9.5.1.1.2 
Medical History .............................................................................52 
9.5.1.1.3 
Other Screening/Baseline Assessments .........................................52 
9.5.1.2 
Efficacy Assessments...........................................................................54 
9.5.1.2.1 
Montreal Cognitive Assessment (MOCA).....................................55 
9.5.1.2.2 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol 
Coding (WAIS-IV DSC)................................................................55 
9.5.1.2.3 
Clinician’s Interview Based Impression of Change Plus 
Caregiver Input (CIBIC-Plus) ........................................................55 
9.5.1.2.4 
Neuropsychiatric Inventory (NPI) .................................................56 
9.5.1.2.5 
Scale for Assessment of Positive Symptoms in Parkinson’s 
Disease (SAPS-PD) .......................................................................56 
9.5.1.2.6 
Mini-Mental State Examination (MMSE) .....................................56 
9.5.1.2.7 
Cognitive Fluctuation Inventory (CFI) ..........................................57 
9.5.1.2.8 
Clinician Global Impression of Change in Dementia With 
Lewy Bodies (CGIC) .....................................................................57 
9.5.1.2.9 
Functional Assessments Questionnaire (FAQ) ..............................57 
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................57 
9.5.1.3.1 
Pharmacokinetic Assessments .......................................................57 
9.5.1.3.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments ...................................................................................58 


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9.5.1.4 
Safety Assessments ..............................................................................59 
9.5.1.4.1 
Adverse Events ..............................................................................59 
9.5.1.4.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................61 
9.5.1.4.3 
Study-Specific Adverse Events......................................................62 
9.5.1.4.4 
Laboratory Measurements .............................................................64 
9.5.1.4.5 
Vital Signs and Weight Measurements ..........................................65 
9.5.1.4.6 
Physical Examinations ...................................................................65 
9.5.1.4.7 
Electrocardiograms ........................................................................66 
9.5.1.4.8 
Other Safety Assessments ..............................................................66 
9.5.2 
Schedule of Procedures/Assessments ..........................................................67 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................67 
9.5.2.2 
Description of Procedures/Assessments Schedule...............................73 
9.5.3 
Appropriateness of Measurements ...............................................................73 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................74 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................74 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................74 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................75 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................75 
9.5.4.3.2 
Reporting of Abnormal Hepatic Tests of Clinical Interest ............76 
9.5.4.4 
Expedited Reporting ............................................................................76 
9.5.4.5 
Breaking the Blind ...............................................................................76 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................76 
9.5.5 
Completion/Discontinuation of Subjects .....................................................77 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................78 
9.5.7 
Confirmation of Medical Care by Another Physician .................................79 
9.6 
Data Quality Assurance .........................................................................................79 
9.6.1 
Data Collection ............................................................................................79 
9.6.2 
Clinical Data Management ..........................................................................79 
9.7 
Statistical Methods .................................................................................................80 
9.7.1 
Statistical and Analytical Plans ....................................................................80 
9.7.1.1 
Study Endpoints ...................................................................................80 
9.7.1.1.1 
Primary Endpoint ...........................................................................80 
9.7.1.1.2 
Secondary Endpoints .....................................................................80 
9.7.1.1.3 
Exploratory Endpoints ...................................................................80 


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9.7.1.2 
Definitions of Analysis Sets.................................................................81 
9.7.1.3 
Subject Disposition ..............................................................................81 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................82 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................82 
9.7.1.6 
Efficacy Analyses ................................................................................82 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................82 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................82 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................83 
9.7.1.8 
Safety Analyses ....................................................................................83 
9.7.1.8.1 
Extent of Exposure .........................................................................83 
9.7.1.8.2 
Adverse Events ..............................................................................84 
9.7.1.8.3 
Laboratory Values ..........................................................................84 
9.7.1.8.4 
Vital Signs ......................................................................................85 
9.7.1.8.5 
Electrocardiograms ........................................................................85 
9.7.1.8.6 
Other Safety Analyses....................................................................85 
9.7.2 
Determination of Sample Size .....................................................................85 
9.7.3 
Interim Analysis ...........................................................................................86 
9.7.4 
Other Statistical/Analytical Issues ...............................................................86 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................86 
10 REFERENCE LIST .........................................................................................................86 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......88 
11.1 
Changes to the Protocol .........................................................................................88 
11.2 
Adherence to the Protocol ......................................................................................88 
11.3 
Monitoring Procedures...........................................................................................88 
11.4 
Recording of Data ..................................................................................................89 
11.5 
Identification of Source Data .................................................................................89 
11.6 
Retention of Records..............................................................................................90 
11.7 
Auditing Procedures and Inspection ......................................................................90 
11.8 
Handling of Study Drug .........................................................................................90 
11.9 
Publication of Results ............................................................................................91 
11.10 Disclosure and Confidentiality ..............................................................................91 
11.11 Discontinuation of Study .......................................................................................91 
11.12 Subject Insurance and Indemnity ...........................................................................92 
12 APPENDICES .................................................................................................................93 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Study E2027-G000-201: Summary of Efficacy of E2027 in Overall 
Population ..................................................................................................31 
Table 2 
Study E2027-G000-201: Summary of Efficacy of E2027 in Subgroups 
With and Without Amyloid Copathology ..................................................32 
Table 3 
Treatment Administered ............................................................................46 
Table 4 
Clinical Laboratory Tests ...........................................................................64 
Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 .............68 
Table 6 
Summary of Estimated Blood and CSF Sample Volumes.........................73 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design for Study E2027-A001-203 .................................................35 
 
LIST OF APPENDICES 
Appendix 1 
Diagnostic Criteria for Probable Dementia With Lewy Bodies and 
Probable Parkinson’s Disease Dementia ...................................................94 
Appendix 2 
Examples of Adverse Events That May Signal Drug Abuse Potential ......96 
Appendix 3 
Sponsor’s Grading for Laboratory Values .................................................98 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
Aβ 
amyloid-β 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
AE 
adverse event 
ApoE 
apolipoprotein E 
β-hCG 
beta-human chorionic gonadotropin 
BP 
blood pressure 
CIBIC-Plus 
Clinician’s Interview Based Impression of Change Plus Caregiver Input 
CIBIS-Plus 
Clinician’s Interview Based Impression of Severity Plus Caregiver Input 
CGIC 
Clinician Global Impression of Change  
cGMP 
cyclic guanosine monophosphate 
CFI 
Cognitive Fluctuation Inventory 
CNS 
central nervous system 
CRA 
Clinical research associate 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
CYP3A 
cytochrome P450 3A 
DAT 
dopamine transporter 
DLB 
dementia with Lewy bodies 
eCRF 
electronic case report form 
ED 
early discontinuation 
FAQ 
Functional Assessments Questionnaire 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GFAP 
glial fibrillary acidic protein 
hCG 
human chorionic gonadotropin 
HPMC 
hypromellose 
HYS 
Hoehn and Yahr Scale 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 
LBD 
Lewy body dementias 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LLN 
lower limit of normal 


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Abbreviation 
Term 
LNH 
low/normal/high 
LP 
lumbar puncture 
LS 
least square 
MDS 
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBG 
123I-meta-iodobenzylguanidine 
MMA 
methylmalonic acid 
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MRI 
magnetic resonance imaging 
NFL 
neurofilament light 
NPI 
Neuropsychiatric Inventory 
NRG 
neuregulin 
PD 
pharmacodynamic(s) 
PDD 
Parkinson’s disease dementia  
PDE9 
phosphodiesterase 9 
PET 
positron emission tomography 
PGx 
pharmacogenomic 
PK 
pharmacokinetic(s) 
PSG 
polysomnography 
PT 
preferred term 
PTT 
partial thromboplastin time 
QD 
once daily 
QTcF 
corrected QT interval calculated using Fridericia’s formula 
REM 
rapid eye movement 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAPS 
Scale for Assessment of Positive Symptoms 
SAPS-PD 
Scale for Assessment of Positive Symptoms in Parkinson’s Disease 
SFQ 
Short Fluctuation Questionnaire 
SOC 
system organ class 
TEAEs 
treatment-emergent adverse events 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UPDRS-III 
Unified Parkinson’s Disease Rating Scale Part III:  Motor Examination 
US 
United States 
WAIS-IV DSC 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol Coding 
WHO DD 
World Health Organization Drug Dictionary 
 


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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 International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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 associates [CRAs], 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. 
Documented 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 (2018)  
• 
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 Technical Requirements for 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 
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 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.  


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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.   
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 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 will be verified by the sponsor and kept on file 
according to local procedures at the site.   
The subject or the subject’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented. 
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 30 investigational sites in the United States (US) and Canada. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in the Investigator 
Study File provided to each site. 
7 
INTRODUCTION 
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 


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(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 approximately 50% to 70% of subjects have concurrent amyloid pathology in the 
brain similar to that in Alzheimer’s disease (AD) (Donaghy, et al., 2015).  In PDD the 
prevalence of concurrent amyloid pathology is lower than DLB, with a positive amyloid 
positron emission tomography (PET) scan in approximately 34% of PDD patients 
(Petrou, et al., 2015).  Patients with DLB or PDD with concomitant AD amyloid and tau 
pathology may have shorter disease duration and shorter survival compared to patients 
without such pathology (Irwin, et al., 2017; Ferman, et al., 2020). 
7.1 
Compound Overview 
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 
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).  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 


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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 a need for further treatment benefit. 
7.1.2 
Therapeutic Pathway 
E2027 is a novel highly selective and potent inhibitor of phosphodiesterase 9 (PDE9).  PDE9 
is primarily responsible for breakdown of cyclic guanosine monophosphate (cGMP) within 
the brain, a second messenger implicated in synaptic plasticity, learning and memory.  
Restoring cGMP levels in the brain of DLB patients without amyloid copathology, by 
inhibiting the PDE9 enzyme, is hypothesized to enhance synaptic plasticity at intact synapses 
and improve cognition.  Recent study results (see below) have prompted the need to conduct 
this study to understand the effect of E2027 in DLB patients with amyloid copathology 
relative to those without amyloid copathology. 
7.2 
Clinical Experience 
E2027 is a new chemical entity.  E2027 has been evaluated in 5 completed studies 
(E2027-A001-001[Study 001], E2027-A001-002 [Study 002], E2027-A001-003 [Study 003], 
E2027-A001-005 [Study 005], and E2027-G000-201 [Study 201]).  In the completed Phase 1 
studies, 176 subjects received at least 1 dose of E2027 (120 subjects administered single 
E2027 doses from 10 to 1200 mg in Study 001, Study 003, and Study 005, and 56 subjects 
administered multiple doses of E2027 from 5 to 400 mg once daily [QD] for up to 6 weeks in 
Study 002).  In the completed Phase 2 study (Study 201), there were 200 subjects with DLB 
randomized in a 1:1 ratio to receive 50 mg of E2027 or placebo administered QD.  
In the Phase 1 studies, E2027 was found to be well-tolerated at doses up to 400 mg QD for 
14 days.  Doses of E2027 at 50 mg QD or higher resulted in mean cerebrospinal fluid (CSF) 
cGMP elevation by approximately 200% from baseline at steady state, which was maintained 
after 6 weeks of treatment.  This implied that >80% of subjects had at least 150% CSF cGMP 
elevation from baseline at a dose of E2027 50 mg QD.  
Detailed description of clinical experience with E2027, including pharmacokinetic (PK), 
pharmacodynamic (PD), metabolism, and safety in Phase 1 studies, is provided in the E2027 
Global Investigator’s Brochure. 
Study 201 was a Phase 2 proof of concept study.  It was a randomized, double-blind, 
placebo-controlled study to determine the efficacy of a dose of E2027 (50 mg QD) compared 
to placebo in subjects with DLB.  The key efficacy endpoints were Montreal Cognitive 
Assessment (MoCA), Clinician’s Interview Based Impression of Change Plus Caregiver 
Input (CIBIC-Plus), Neuropsychiatric Inventory (NPI-12), and Cognitive Fluctuation 
Inventory (CFI).  Details of the study design of are provided in the E2027 Global 
Investigator’s Brochure. 
In Study 201, there were 99 subjects with mild to moderate DLB treated with E2027 50 mg 
QD and 97 subjects treated with placebo for up to 12 weeks.  E2027 was well-tolerated.  
Most cases of treatment-emergent adverse events (TEAEs) were mild or moderate in 


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severity.  The incidence of severe TEAEs was higher in placebo than E2027 (placebo [6.2%], 
E2027 [2.0%]).  The most common TEAEs in subjects on E2027 were fall (10.1%), visual 
hallucinations (7.1%), worsening of DLB (5.1%), dizziness (5.1%), and nasopharyngitis 
(5.1%).  The most common TEAEs in subjects on placebo were fall (15.5%), visual 
hallucination (9.3%), and urinary tract infection (5.2%). 
The TEAEs with higher incidence in the E2027 group (>2% and at least 2-fold of that in 
placebo group) were worsening of DLB (5.1%, compared with 1.0% on placebo), dizziness 
(5.1%, compared with 1.0% on placebo), somnolence (3.0%, compared with 1.0% on 
placebo), orthostatic hypotension (3.0%, compared with 1.0% on placebo) and aggression 
(3.0%, compared with no subjects on placebo).  
The incidence of specific treatment-related TEAEs across the treatment groups was generally 
similar except for a higher incidence in the E2027 group of worsening of DLB, with 1 (1.0%) 
subject in the placebo group and 5 (5.1%) subjects in the E2027 group.  The incidence of 
mild, moderate and severe treatment-related TEAEs was similar in the placebo group and the 
E2027 group.   
One death occurred during the study, after the final dose; this subject was in the placebo 
group.  No deaths were reported in the E2027 group.  A similar percentage of subjects in 
each treatment group experienced nonfatal other treatment-emergent serious adverse events 
(SAEs):  9 (9.3%) subjects in the placebo group and 7 (7.1%) subjects in the E2027 group.   
There were no clinically significant changes in laboratory test findings, ECGs, Columbia 
Suicide Severity Rating Scale (C-SSRS), Unified Parkinson’s Disease Rating Scale Part III: 
Motor Examination (UPDRS-III), or vital signs (including orthostatic hypotension and 
orthostatic tachycardia).  
In Study 201, proof of concept was not achieved in the overall study population.  There was 
no treatment benefit of E2027 compared with placebo in the various efficacy endpoints after 
12 weeks of treatment, including MoCA, CIBIC-Plus, NPI-12, and CFI.  The treatment 
differences between E2027 and placebo with their confidence intervals are summarized in 
Table 1. 


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Table 1 
Study E2027-G000-201: Summary of Efficacy of E2027 in Overall 
Population 
Efficacy Endpoint 
At 12 Weeks 
Treatment Difference (95% CI)a 
MoCAb 
0.181 (-0.716, 1.078) 
CIBIC-Plusc 
1.018 (0.695, 1.492) 
NPI-12d 
-0.964 (-4.717, 2.788) 
CFId 
-0.043 (-0.890, 0.804) 
CFI = Cognitive Fluctuation Inventory, CIBIC-Plus = Clinician’s Interview Based Impression of Change Plus 
Caregiver Input, GLMM = generalized linear mixed models, LS = least square, MMRM = mixed effects model 
of repeated measures, MoCA = Montreal Cognitive Assessment, NPI = Neuropsychiatric Inventory. 
a:  Treatment difference (E2027 minus Placebo) for MoCA, NPI, and CFI is LS means from MMRM analysis.  
CIBIC-Plus treatment difference is the proportional odds ratio from a GLMM analysis. 
b: Positive treatment difference indicates treatment benefit on E2027.  
c:  Odds ratio >1 indicates treatment benefit on E2027. 
d:  Negative treatment difference indicates treatment benefit on E2027. 
There was a suggestion that subjects who did not take AChEI at baseline showed numerically 
higher treatment benefit in MoCA and CIBIC-Plus than subjects who took AChEI at 
baseline.   
There were 4 subjects who participated in the optional CSF substudy and they were all 
treated with E2027.  Their CSF cGMP mean change from baseline showed an increase by 
168%.  There appeared to be a correlation between their CSF cGMP percentage change from 
baseline with their change from baseline in MoCA and CIBIC-Plus.  There was a trend that 
subjects with lower CSF cGMP percentage change from baseline having less improvement or 
worsening of their MoCA from baseline, whereas subjects with higher CSF cGMP 
percentage change from baseline showed greater improvement in MoCA from baseline.  
Similarly, subjects with higher CSF cGMP percentage change from baseline showed mild 
improvement or no change in CIBIC-Plus, whereas those with lower CSF cGMP percentage 
change from baseline showed mild worsening. 
As AD-type copathology of amyloid in the brain in DLB is common (occurring in 
approximately 70% of subjects), plasma amyloid Aβ42/Aβ40 ratio was determined in a 
subpopulation of subjects in Study 201 (n=113) using the C2N Preclivity assay.  A low 
plasma Aβ42/Aβ40 ratio is known to be associated with amyloid deposition in the brain in 
subjects with AD as shown by amyloid positive PET scans (Doecke, 2020).  The C2N 
Preclivity assay has 85% sensitivity and 68% specificity for detecting elevated brain amyloid 
in amyloid PET scans (based on visual read of the scans) in subjects with mild cognitive 
impairment or mild dementia due to AD (based on data from Eisai’s Mission AD Study).  
Using a cut-off plasma Aβ42/Aβ40 ratio of 0.092 (derived from correlation analysis of 
plasma Aβ42/Aβ40 ratio with amyloid load on PET scan in Eisai’s Mission AD Study), 
subjects with a ratio <0.092 were defined as a subgroup of DLB with amyloid copathology 
(n=57, approximately 50% of subjects with plasma amyloid ratio data), whereas subjects 
with a ratio ≥0.092 were defined as a subgroup of DLB without amyloid copathology (n=56, 


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approximately 50% of subjects with plasma amyloid ratio data).  Efficacy analyses were 
performed on various endpoints in these 2 subgroups.  It was found that numerically there 
was a trend for treatment benefit of E2027 compared with placebo in the subgroup of DLB 
without amyloid copathology, in MoCA, CIBIC-Plus, and Clinician Global Impression of 
Change (CGIC), but there was no treatment difference in the CFI and NPI.  In the subgroup 
of DLB with amyloid copathology, it was considered that there was no treatment benefit of 
E2027 in MoCA, CIBIC-Plus, CGIC, and CFI, whereas in the NPI there was numerically less 
worsening from baseline than placebo.  None of these treatment differences in either 
subgroup was statistically significant, but in the DLB subgroup without amyloid 
copathology, the treatment benefit of E2027 on MoCA was close to nominal statistical 
significance (P=0.0534).  The treatment differences between E2027 and placebo with their 
confidence intervals are summarized below for each subgroup (Table 2). 
Table 2 
Study E2027-G000-201: Summary of Efficacy of E2027 in 
Subgroups With and Without Amyloid Copathology 
Efficacy Endpoint 
After 12 Weeks 
Without Amyloid Copathology 
Treatment Difference 
(95% CI)a 
With Amyloid Copathology 
Treatment Difference 
(95% CI)a 
MoCAb 
1.567 (-0.024, 3.157) 
-0.178 (-1.890, 1.534) 
CIBIC-Plusc 
1.596 (0.753, 3.386) 
1.022 (0.478, 2.184) 
NPId 
-0.073 (-6.370, 6.224) 
-2.757 (-10.095, 4.581) 
CFId 
-0.523 (-2.154, 1.109) 
0.333 (-1.489, 2.155) 
CGIC-DLBc 
1.170 (0.555, 2.464) 
0.620 (0.288,1.339) 
CFI = Cognitive Fluctuation Inventory, CIBIC-Plus = Clinician’s Interview Based Impression of Change Plus 
Caregiver Input, CGIC-DLB = Clinician Global Impression of Change in Dementia with Lewy Bodies, 
GLMM = generalized linear mixed models, LS = least square, MMRM = mixed effects model of repeated 
measures, MoCA = Montreal Cognitive Assessment, NPI = Neuropsychiatric Inventory. 
a:  Treatment difference (E2027 minus Placebo) for MoCA, NPI, and CFI is LS means from MMRM analysis.  
CIBIC-Plus treatment difference is the proportional odds ratio from a GLMM analysis. 
b:  Positive treatment difference indicates treatment benefit on E2027.  
c:  Odds ratio >1 indicates treatment benefit on E2027. 
d:  Negative treatment difference indicates treatment benefit on E2027. 
7.3 
Study Rationale 
Cyclic nucleotides such as cyclic adenosine monophosphate and cGMP work as second 
messengers in the intracellular signaling cascade, and play a critical role in learning, memory 
function and induction of hippocampal long-term potential in animal models 
(Domek-Łopacińska and Strosznajder, 2005).  Therefore, increase of cGMP in synaptic 
regions is expected to enhance long-term potential and consequently 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 such as E2027 may be efficacious in neurodegenerative diseases with cognitive 
impairment such as DLB and PDD.   


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Amyloid deposition leads to tau aggregation in neurons and both pathological processes 
interact synergistically (reviewed in Busche and Hyman, 2020).  Specifically, synaptic 
degeneration due to amyloid and tau accumulation lead to impairment of the cGMP synthesis 
pathway on the postsynaptic side (Monfort and Felipo, 2010; Park et al., 2020).  Thus, intact 
synapse may be required for optimal increase of cGMP by E2027, since both presynaptic and 
postsynaptic elements are involved. 
It has been found that in DLB subjects with amyloid copathology, their whole brain and 
hippocampal atrophy rates were similar to AD subjects, whereas DLB subjects without 
amyloid copathology showed slower brain atrophy rates comparable to healthy age-matched 
subjects (Nedelska et al., 2015).  Thus, in DLB subjects with amyloid copathology, there 
occurs greater neuronal and synaptic degeneration compared to DLB subjects without 
amyloid copathology.  There may be relative preservation of hippocampal synapses that 
respond to PDE9 inhibition better in DLB subjects without amyloid copathology and those 
who have amyloid copathology.  
Thus, it is proposed that subjects with DLB with amyloid copathology may have lower 
response to E2027 in terms of brain cGMP elevation compared to DLB subjects without 
amyloid copathology.  This may then manifest as lower CSF cGMP in DLB subjects with 
amyloid copathology than DLB subjects without amyloid copathology.  Furthermore, a lower 
brain cGMP response to E2027 in DLB subjects with amyloid copathology may lead to lower 
efficacy in cognitive endpoints than DLB subjects without amyloid copathology, as 
suggested by the trends in Study 201.  As PDD and DLB are considered part of the same 
continuum of LBD, it is possible that subjects with PDD with and without amyloid 
copathology may also respond differently to E2027 treatment.  
The proposed study (E2027-A001-203; Study 203) is an open-label study to evaluate the 
different responses to E2027 in subjects with DLB and PDD who have or do not have 
amyloid copathology in terms of their CSF cGMP elevation and various cognitive and 
neuropsychiatric endpoints.  The presence of absence of amyloid copathology will be 
established by their plasma amyloid-β (Aβ)42/Aβ40 ratio (as in Study 201) using the C2N 
Preclivity assay.  
It will also evaluate the safety, tolerability, PK, and other PD effects in biomarkers of E2027 
in these subjects.  The relationship between CSF cGMP increase and change in efficacy 
endpoints will be explored.  If it is found that in subjects without amyloid copathology there 
is greater increase in CSF cGMP, associated with improvement in efficacy endpoints, 
whereas in subjects with amyloid copathology there is less increase in CSF cGMP associated 
with worsening or no change in efficacy endpoints, then such a correlation will corroborate 
the results of Study 201 and support the theory that amyloid status affects E2027 drug 
response and downstream efficacy.  The results will guide the selection of subgroups of DLB 
and PDD subjects (as characterized by presence or absence of amyloid copathology, or other 
biomarker-defined characteristics) for further evaluation of efficacy of E2027 in Phase 3 
studies. 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to demonstrate the PD effects of E2027 on CSF cGMP 
in subjects with DLB and PDD with and without amyloid copathology after 9 weeks of 
treatment. 
8.2 
Secondary Objective 
The secondary objective of the study is to evaluate the safety and tolerability of E2027 in 
subjects with DLB and PDD. 
8.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• 
To evaluate the efficacy of E2027 on the following endpoints after 12 weeks of 
treatment: 
- 
Montreal Cognitive Assessment (MoCA) 
- 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol Coding (WAIS-IV DSC) 
- 
Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) 
- 
Clinician Global Impression of Change (CGIC) 
- 
Cognitive Fluctuation Inventory (CFI) 
- 
Mini-Mental State Examination (MMSE) 
- 
Neuropsychiatric Inventory (NPI) 
- 
Scale for Assessment of Positive Symptoms in Parkinson’s Disease (SAPS-PD) 
- 
Functional Assessments Questionnaire (FAQ) 
• 
To explore the indirect PD effects of E2027 on plasma biomarkers and CSF biomarkers 
related to DLB and PDD 
• 
To explore the effects of E2027 on CSF cGMP, other plasma and CSF biomarkers, and 
clinical endpoints using other diagnostic subgroups classifications based on baseline 
biomarkers  
• 
To characterize the population PK of E2027 in subjects with DLB or PDD, including 
evaluation of the effects of intrinsic and extrinsic factors on the PK 
• 
To explore the relationships amongst the PK exposure of E2027 in plasma/CSF and its 
effects on plasma/CSF biomarkers (including CSF cGMP) as well as clinical efficacy and 
safety endpoints  
• 
To explore the relationship amongst plasma and CSF biomarkers at baseline and after 
treatment with E2027  
• 
To collect genomic samples for exploratory investigation on heterogeneity in 
drug-response and clinical features of disease 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multicenter, open-label study in subjects with DLB or PDD who will be treated with 
E2027 for 12 weeks.  Four subgroups of subjects will be enrolled as follows:  DLB without 
amyloid copathology, DLB with amyloid copathology, PDD without amyloid copathology, 
and PDD with amyloid copathology.  The presence of amyloid copathology is defined as 
ratio of plasma concentration of Aβ42/Aβ40 <0.092 (based on the C2N Preclivity assay).   
The study design allows for add-on therapy of E2027 to standard of care for DLB and PDD, 
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 to participate in this study but are not permitted to start such medications 
during the study.  It is required that in each subgroup there should be at least 1 subject who is 
not receiving AChEI or memantine during the study.  Subjects should be on stable doses of 
medications for the treatment of Parkinson’s disease, maintained without change during the 
study. 
For all subjects, study participation will comprise 2 phases:  Pretreatment Phase and 
Treatment Phase.  The Pretreatment Phase will include a Screening Period and a Baseline 
Period.  The Treatment Phase will include a Treatment Period and Follow-up Period.  An 
overview of the study design is presented in Figure 1. 
 
Figure 1 
Study Design for Study E2027-A001-203  
QD = once daily, Sd = Start of study drug (E2027) 
Period: 
Sd 
E2027 50 mg QD 
Day -49 to -8 
Day 1 
12 weeks: Day 1 to 84 
Phase: 
Screening 
4 weeks 
Pretreatment 
Baseline 
Day -7 to -1 
Treatment 
Follow-up 
Treatment 
Treatment 


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9.1.1 
Pretreatment Phase 
The Pretreatment Phase will last up to 7 weeks and will include a Screening Period (up to 
6 weeks) and a Baseline Period (up to 1 week).   
9.1.1.1 
Screening Period 
Screening will occur between Day -49 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 ECGs.   
Subjects with DLB 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.   
Subjects with PDD will be assessed on clinical scales of cognition and depression, safety 
MRI of the brain and DAT brain imaging or MIBG (if indicated in individual subjects and 
not previously performed) to support their diagnosis of Parkinson’s disease (and not other 
extrapyramidal or cerebrovascular diseases).   
During Screening, the subject’s motor features will be assessed on the Movement Disorders 
Society (MDS) UPDRS-III and staged by the Hoehn and Yahr Scale (HYS).  History of 
suicidality will be assessed by the C-SSRS.  Medical history 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 subject safety or study 
procedures. 
Eligibility assessments at Screening will be conducted in 6 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, PDD and other 
medical conditions) and prior 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 then Geriatric 
Depression Scale (GDS) should be done first, followed by the MoCA.  The caregivers or 
informants will also complete the Short Fluctuation Questionnaire (SFQ), CFI, and NPI.  
If the eligibility criteria regarding the MMSE and GDS are not met, the other assessments 
(SFQ, CFI, and NPI) do not have to be performed and the subject should be screen failed.   


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• 
In Tier 3, subjects will be assessed with the Modified Hachinski Ischemic Scale, 
UPDRS-III, HYS, and C-SSRS.  A plasma sample will be collected to measure 
biomarkers related to AD copathology (amyloid, phosphorylated-tau [p-tau]) and other 
biomarkers related to DLB or PDD.  If a sufficient number of subjects in a subgroup has 
been achieved, a new subject in that subgroup will be screen failed at Tier 3 or at 
subsequent tiers.  While waiting for the result of the subject’s plasma Aβ42/Aβ40 ratio, 
the subject may proceed with subsequent tiers.   
• 
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, CFI, 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 or PDD 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 or PDD, 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 3 months and a subject should not be rescreened 
more than 2 times under the same version of the eligibility criteria.  For subjects who screen 
fail at Tier 3 or 4 due to their subgroup already having achieved the target number of 
subjects, they may be rescreened if a new subject is required in their subgroup due to early 
discontinuation.  If this rescreening occurs within 30 days after screen fail, the history of 
DLB or PDD in Tier 1 and the assessments at Tiers 2, 3, and 4 do not need to be repeated 
unless clinically indicated in the investigator’s judgement. 
All subjects who have completed screening assessments in Tiers 1 to 6 and are deemed 
eligible for the study will have a baseline CSF sample collected by lumbar puncture (LP).  
The CSF sample will be collected in the morning, either in the fasted state or at least 2 hours 
after breakfast.  In subjects who require DAT or MIBG scan, the CSF collection should be at 
least 1 week after the scan. 
9.1.1.2 
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) and at least 1 week after CSF collection.  Study assessments should 
be conducted in the morning (whenever possible).  Cognition will be assessed by the MoCA, 


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which must be the first clinical scale to be administered before any invasive procedures, 
followed by the WAIS-IV DSC and then the Clinician Interview Based Impression of 
Severity Plus Caregiver Input (CIBIS-Plus).  The caregiver or informant will also complete 
the CIBIS Plus, NPI, CFI, SAPS-PD, and FAQ.  The rater administering the CIBIS-Plus 
should be independent of the rater(s) who administer the other clinical scales.   
At the Baseline Visit subjects will be assessed regarding other medical conditions and 
concomitant medications (including medications for DLB or PDD) 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 assessments including vital signs, ECGs, laboratory 
tests, and C-SSRS will also be conducted. 
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase. 
9.1.2 
Treatment Phase 
The Treatment Phase will last up to 16 weeks and will include a Treatment Period (up to 
12  weeks) and a Follow-up Period (up to 4 weeks). 
9.1.2.1 
Treatment Period 
After completing study assessments at the Baseline Visit, subjects who continue to be 
eligible will proceed to the Treatment Period on E2027 (50 mg QD).  They will be provided 
with 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 3, 6, 9, and 12 weeks on E2027.  Efficacy assessments will be performed after 6 and 
12 weeks on E2027 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 efficacy assessment to be administered, followed by the WAIS-IV DSC (after 12 weeks 
only), then the CIBIC-Plus and finally the MMSE (after 12 weeks only).  Whenever possible, 
a subject should have the same rater administering the MoCA and the CIBIC-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 caregiver or 
informant will also complete the CIBIC-Plus, NPI, CFI, SAPS-PD (after 12 weeks only) and 
FAQ (after 12 weeks only).  Safety assessments will be conducted at these visits, including 
review of 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 and 
12 weeks on study drug and formulate the CGIC of the subject’s clinical status from baseline.   
After subjects have completed 9 weeks of treatment with E2027 will have a 2nd CSF sample 
collected.  The CSF sample will be collected in the morning at approximately the same time 
as at Screening, either in the fasted state or at least 2 hours after breakfast. A 2nd plasma 
sample for biomarkers will also be collected. 
If during the study, the designated caregiver or informant relinquishes his/her responsibilities 
as caregiver or informant, a replacement caregiver or informant must be found.  It is 


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recommended that this replacement caregiver or informant should meet the criteria above and 
have similar knowledge of the subject’s clinical status from Baseline throughout the 
Treatment Period.  If a replacement caregiver or informant is found who does not meet the 
criteria above, then the CIBIC-Plus will not be conducted but subject may continue in the 
study.  If no replacement caregiver or informant is available at all the subject must be 
discontinued from the study. 
9.1.2.2 
Follow-Up Period 
After the Treatment Period, subjects will complete a Follow-Up Visit 4 weeks after the final 
dose of study drug.  Safety assessments will be completed.   
The end of study is defined as the last subject completing the Follow-Up Visit. 
9.1.3 
Conduct of the Study During the COVID-19 Pandemic and Other 
Extenuating Circumstances 
All study assessment and visit information affected by any extenuating circumstances 
(eg, the COVID-19 pandemic) will be collected on the electronic case report forms (eCRFs).  
These include but are not limited to any visits or assessments that are missed or not done, any 
assessments that are performed remotely/offsite or in person/onsite, and any home delivery 
of investigational product. 
During the COVID-19 pandemic, and under other extenuating circumstances: 
• 
An extension of the Screening Period from 6 weeks to up to 10 weeks is allowed with 
sponsor approval on a subject by subject basis. 
• 
If subjects cannot visit the study site, all procedures which require physical contact with 
the subjects (eg, vital signs, ECGs, blood tests, physical examination, UPDRS-III) may 
be conducted via home visit (if feasible) with sponsor approval.  The brain or cardiac 
imaging during the Screening Visit must be conducted at the study site.  The CSF 
collection at the Screening Visit and Visit 6 (Week 9) must be conducted at the study site.  
Other study procedures including all the efficacy endpoints, AEs, and concomitant 
medications review may be conducted remotely via telephone, sponsor approved 
telehealth, or home visit.  If it is not possible for subjects to attend the study site for the 
CSF collection Visit 6 (Week 9), this can be performed at an Unscheduled Visit as soon 
as possible after Week 9.  Study drug may be delivered to subjects’ homes if it is not 
possible to visit the study site to collect the study drug.   
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is an open-label study to evaluate the responses to E2027 in CSF cGMP and efficacy 
endpoints in subjects with DLB or PDD with and without amyloid copathology.  The study is 
open label on E2027 because the main comparison is between subgroups of subjects with and 
without amyloid copathology rather than comparing against placebo.  


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Subjects with DLB and PDD will be eligible for this study because DLB and PDD are 
considered as 2 ends of the same spectrum of LBD with similar clinical features but with 
different temporal sequence of onset (Aarsland, et al., 2003; Walker, et al., 2015).  In a 
clinical trial of memantine in LBD, subjects with both diagnostic categories were enrolled 
(Aarsland, et al., 2009).  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 supports investigating both ends of the LBD spectrum 
within Study 203.  Any differential responses to E2027 between subjects with and without 
amyloid copathology may be seen in both DLB and PDD.  Therefore, in this study equal 
numbers of subjects in each of the 4 subgroups (DLB without amyloid copathology, DLB 
with amyloid copathology, PDD without amyloid copathology and PDD with amyloid 
copathology) will be enrolled.  
AChEIs are the current standard treatments for LBD (Walker, et al., 2015); as such, subjects 
who are established on a stable dose of AChEIs are eligible.  As not all subjects will receive 
AChEI as standard of care, subjects who are not taking AChEI are also eligible.  In Study 
201, it appeared that subjects not taking AChEI (~20% of randomized subjects) had greater 
numerical treatment benefit than subjects taking AChEI (~80% of randomized subjects).  
Therefore, in Study 203 each of the 4 subgroups is required to have at least 1 subject not 
taking AChEI to be representative of the Study 201 population.  The treatment duration with 
E2027 is 12 weeks.  These study design features are the same as in Study 201 such that 
Study 203 will be able to further evaluate or corroborate the results in Study 201.  
The primary endpoint is the percentage change from baseline of CSF cGMP, which is the 
main PD response to E2027 that may show different responses in subjects with and without 
amyloid copathology.  As it is an objective endpoint, it supports the use of an open-label 
design.  The efficacy endpoints are exploratory endpoints, and they include the MoCA, 
CIBIC-Plus, CFI, MMSE, NPI, and CGIC which were the efficacy endpoints in Study 201.  
The use of the same efficacy endpoints after 12 weeks of treatment as in Study 201 enables 
Study 203 to corroborate the pattern of changes seen in these endpoints on E2027 in 
Study 201. 
For evaluating the CSF cGMP elevation from baseline, CSF samples will be collected at 
baseline and again after 9 weeks of treatment on E2027 as in Study 201. In Study 002, it was 
found that CSF cGMP elevation from baseline was similar after 2 weeks and 6 weeks of 
treatment on E2027, and hence it is considered that after 9 weeks of treatment CSF cGMP 
elevation will have reached steady state in Study 203.  CSF collection and efficacy 
evaluations will be conducted at separate visits (CSF collection after 9 weeks and efficacy 
endpoints after 12 weeks of treatment) to avoid CSF collection interfering with subjects’ 
performance in the efficacy evaluations.   
In Study 002, the CSF cGMP increased with increasing dose, approaching a saturation level 
of approximately 200%, which was considered sufficient for procognitive effects based on 
animal models.  In Study 201, the limited data suggested that in this study population 
(comprising DLB subjects with and without amyloid copathology) the CSF cGMP elevation 
could be approximately 170% with no overall clinical benefit on cognition.  Furthermore, 


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based on the limited data of the correlation between CSF cGMP percentage change from 
baseline and change in efficacy endpoints, it was found that subjects with 190% to 200% 
increase from baseline in CSF cGMP showed improvement in MoCA and CIBIC-Plus, 
whereas subjects with <170% increase from baseline in CSF cGMP showed no improvement 
or worsening in these efficacy endpoints.  Thus, it is considered that in subjects without 
amyloid copathology, if their CSF cGMP elevation is >30% higher than in subjects with 
amyloid copathology, this may be associated with clinically significant differences in 
efficacy as suggested by the subgroup results in Study 201.  The absolute concentrations of 
CSF cGMP attained after treatment on E2027 between subjects with and without amyloid 
copathology will also be investigated for potential contribution to the difference in efficacy. 
Pharmacogenomic blood samples will be collected to explore if genotypes associated with 
development or progression of DLB or deposition of amyloid copathology affect the CSF 
cGMP response to E2027. 
9.3 
Selection of Study Population 
Approximately 64 subjects will be screened at approximately 30 investigational sites in the 
US and Canada to provide a maximum of 32 treated subjects, with 8 subjects in each of the 
4 subgroups (DLB without amyloid copathology, DLB with amyloid copathology, PDD 
without amyloid copathology, and PDD with amyloid copathology).  Allowing for a 25% 
dropout rate there will be 24 treated subjects completing the study treatment, with 6 subjects 
in each subgroup.  Further subjects may be screened and treated with E2027 if there are less 
than 6 completers in any of the subgroups. 
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug. 
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]) or meet criteria for probable PDD (as defined by the task force of 
the Movement Disorder Society) (Appendix 1).  Specific situations regarding the use of 
imaging are described below: 
a. DLB subjects who have 1 core clinical feature only by the investigator and who do 
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. DLB subjects who 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 do 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. 


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c. DLB subjects who have 2 or more core clinical features by the investigator and the 
central reviewer and who do 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. 
d. PDD subjects with clinical features that are consistent with the diagnostic criteria of 
probable PDD but in whom the investigator considers that there may be other 
diagnoses, DAT brain imaging scan or MIBG scan may be conducted after discussion 
with the sponsor medical monitor. 
3. MMSE >14 and <26 at Screening Visit 
4. For DLB subjects, have experienced visual hallucinations since onset of their DLB   
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.   
7. If receiving Parkinson’s disease medications, must have been on a stable dose for at least 
4 weeks before Screening Visit, with no plans for dose adjustment during the study. 
8. 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.  
9. 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. 


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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 or PDD, including any comorbidities detected 
by clinical assessment or MRI (identification of amyloid copathology is not exclusionary) 
2. History of transient ischemic attacks or stroke within 12 months of Screening 
3. Modified Hachinski Ischemic Scale >4 
4. Parkinsonian (extrapyramidal) features with HYS 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  
6. GDS score >8 
7. Severe visual or hearing impairment that may interfere with the subject study assessments 
including cognitive testing 
8. The following exclusions apply in relation to CSF sampling by LP:   
a. 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]) 
b. Any contraindications to LP (eg, lower spinal malformation on physical examination, 
local spinal infection or other abnormality, obesity to the extent that it makes LP 
technically difficult, or inability to cooperate with LP due to cognitive impairment or 
motor symptoms) 
9. History of deep brain stimulation or other neurosurgical procedure for Parkinson’s 
disease 
10. Has 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. 
11. 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).  Low levels of vitamin B12 may be confirmed 
with reflex testing to include methylmalonic acid (MMA) analysis, (if available in 
region) and excluded only if MMA levels are also >ULN. 
12. 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 PET 
scanning as per local guidelines need not be excluded 
13. Evidence of other clinically significant lesions that suggest a dementia diagnosis other 
than DLB or PDD 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 and will be read by an approved centralized reader. 


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14. 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) 
15. Hypersensitivity to E2027 or any of the excipients   
16. 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)   
17. 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 
18. 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:   
a. Physical examination, ECG, vital signs at Screening or Baseline Visit 
b. Laboratory tests at Screening Visit 
19. 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.   
20. 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   
21. 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. 
22. 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 
23. Taking any of the prohibited medications or not meeting the requirements regarding 
stable doses of permitted medications 
24. Participation in a clinical study involving any investigational drug/device for DLB or 
PDD 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 
25. 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 


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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. 
26. Males who have not had a successful vasectomy (confirmed azoospermia) if their female 
partners are of childbearing potential and are not willing to use a highly effective 
contraceptive method throughout the study period and for 98 days after study drug 
discontinuation.  No sperm donation is allowed during the study period and for 98 days 
after study drug discontinuation. 
27. 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. 
28. Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following: 
- 
total abstinence (if it is their preferred and usual lifestyle) 
- 
an intrauterine device or intrauterine hormone-releasing system  
- 
a contraceptive implant 
- 
an oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on 
the same dose of oral contraceptive throughout the study and for 28 days after 
study drug discontinuation.) 
- 
have a vasectomized partner with confirmed azoospermia 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation 
(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].) 
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. 
Subjects who prematurely discontinue study treatment for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their final dose of study treatment.  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 treatment 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 


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least 1 originally scheduled visit after the ED Visit.  At these originally scheduled visits that 
take place after the ED Visit, blood PK samples, plasma biomarker samples, and CSF 
samples will not be collected.   
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study treatment 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 
9.4.1 
Treatment Administered 
E2027 will be administered in size #2 hypromellose (HPMC) capsules containing 25 mg of 
E2027.   
All subjects will take 2 × E2027 25 mg capsules QD for a total dose of 50 mg daily for up to 
12 weeks (Table 3). 
Table 3 
Treatment Administered 
Drug Name 
Strength 
Oral Dose Form 
Number Dispensed and Frequency 
Duration 
E2027 
25 mg 
Capsule 
2 × 25 mg capsule QD 
12 weeks 
QD = once daily 
 
9.4.2 
Identity of Investigational Product(s) 
E2027 will be supplied by the sponsor in labeled containers. 
9.4.2.1 
Chemical Name 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 
Not applicable.  


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9.4.2.3 
Labeling for Study Drug 
E2027 will be labeled in accordance with text that is in full regulatory compliance. 
9.4.2.4 
Storage Conditions 
E2027 will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive E2027.  There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
Based on animal cognition models, a sustained increase in CSF cGMP from baseline by 
150% or higher after dosing to steady state is thought to be required for clinical efficacy.  In 
Study 201 a dose of E2027 at 50 mg QD was found to have achieved mean CSF cGMP 
increase from baseline by 168%.  This dose also showed a trend to treatment benefit in the 
MoCA in DLB subjects without amyloid copathology, and it may be sufficient for 
precognitive effects in this subgroup of subjects without amyloid copathology, consistent 
with the animal cognition models.  This dose was also found to be well-tolerated in 
Study 201, with similar incidence of TEAEs and no clinically significant changes in 
laboratory test findings, ECGs, C-SSRS, UPDRS-III, or vital signs (including orthostatic 
hypotension and orthostatic tachycardia).  Therefore, the dose of E2027 in Study 203 is 
selected to be 50 mg QD as in Study 201. 
9.4.5 
Selection and Timing of Dose for Each Subject 
E2027 will be administered orally, QD, in the morning with or without food.  Study 
treatment will begin on Day 1 will continue for 12 weeks.  Subjects should withhold 
administration of E2027 in the morning of the study visit days that blood will be drawn in the 
clinic for PK analysis (Table 5).  Subjects will be instructed to take their other concomitant 
medications at the usual time. 
9.4.6 
Blinding 
The study treatment will not be blinded. 


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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 AE 
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 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 (CYP3A), 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 msec (Exclusion Criterion 16).   
• 
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  
• 
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 of treatment 
with E2027   


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The following restrictions apply to AChEIs (including donepezil, rivastigmine, galantamine) 
or memantine for treatment of DLB or PDD: 
• 
If a subject is already receiving AChEI or 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 AChEI or memantine at Screening, then these should 
not have been used at least 12 weeks before Screening and AChEI or memantine should 
not be started during the study until the Follow-Up Visit. 
• 
Subjects who start AChEI/memantine or change their dose of AChEI/memantine during 
the study should undertake an Unscheduled Visit before making such changes in their 
AChEI/memantine medications to undertake efficacy assessments (MoCA, CIBIC-Plus, 
NPI, CFI, CGIC) (unless they have been conducted within past 4 weeks).  This change in 
AChEI/memantine medications 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 the Statistical Analysis Plan (SAP).  
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, and the handling of efficacy data collected after the change of these 
medications in the efficacy analyses is described in the SAP.   
The following restrictions apply to medications for antipsychotic or neuroleptic drugs, 
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. 
• 
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, NPI, CFI, CGIC) (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 the SAP.   


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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 should 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 medications required for performing LP for CSF sampling are permitted. 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 
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, 
or a completed Investigator and Site Information Form 
• 
Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572 or Investigator and Site Information Form 
• 
A signed and dated curriculum vitae (CV) of the principal investigator including a copy 
of the principal investigator’s current medical license or medical registration number on 
the CV 
• 
A signed and dated clinical studies agreement 


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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 Good Clinical Practice (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, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study drugs 
that occurs at the site, if applicable.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority.  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. 


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9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Screening Assessments 
After the subject has provided informed consent, screening assessments will be performed in 
6 tiers as noted in Table 5.  All assessments and procedures in each tier should be completed, 
and eligibility to continue confirmed, before any assessments/procedures from the next tier 
commence.  
9.5.1.1.1 DEMOGRAPHY  
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/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. 
9.5.1.1.2 MEDICAL HISTORY 
Medical and surgical history, prior and concurrent medications including AChEI and 
memantine use, and current medical conditions will be recorded at the Screening Visit.  All 
medical and surgical history within 5 years must be noted in the Medical History and Current 
Medical Conditions eCRFs.  Medical history will include history of DLB or PDD. 
9.5.1.1.3 OTHER SCREENING/BASELINE ASSESSMENTS 
The following tests will be performed during Screening or at the Baseline Visit (see Table 5):  
GDS, SFQ, Modified Hachinski Ischemic Scale, HYS, safety brain MRI, DAT brain imaging 
and myocardial MIBG scan, vitamin B12 and thyroid function blood tests, urine drug screen, 
pregnancy tests (as appropriate), and collection of PGx blood sample. 
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 or 
PDD 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 


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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 and PDD. 
Modified Hachinski Ischemic Scale 
The modified Hachinski Ischaemic Scale roughly quantifies elements of the history and 
physical examination relevant to the risk of vascular dementia and helps differentiate 
between Alzheimer’s type dementia and multi-infarct dementia.  The questionnaire provides 
for scoring for abrupt onset of dementia, history of stroke, focal neurological signs and 
symptoms, stepwise deterioration, somatic complaints,  emotional incontinence, and 
hypertension (past or present).  The higher the score, the greater the risk of vascular 
dementia.  Subjects with Modified Hachinski Ischemic Scale >4 are excluded. 
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.   
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 causes other than DLB or PDD (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 DAT in the brain is administered.  It is used to visualize the levels of DAT in the 
striatum (caudate and putamen) using single-photon emission computed tomography brain 
imaging.  In subjects with Parkinsonian syndromes including DLB and PDD, there is reduced 
DAT signal in the scan in the striatum (caudate and putamen).  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 one 
of the eligibility criteria.  
MIBG Myocardial Scan  
In this cardiac scan, an intravenous radiopharmaceutical 123I-MIBG that is selectively taken 
up via the norepinephrine transporter into the post-ganglionic sympathetic nerve terminals in 


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the heart is administered.  Uptake into these sympathetic nerve terminals is then visualized 
using single-photon emission computed tomography imaging.  In subjects with Parkinsonian 
syndromes including DLB and PDD, 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.  
Pregnancy Test 
A serum β-hCG test will be performed at Screening and urine β-hCG test will be performed 
at Baseline for female subjects who are <60 years of age and not surgically sterilized.   
Urine Drug Test 
A urine sample will be collected at Screening.  This sample will be tested for common drugs 
of use/abuse: eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine (PCP), 
nicotine/cotinine, opioids (as a group), benzodiazepines, barbiturates, and amphetamines.  
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. 
Height Measurement 
Height (cm) will be recorded at the Screening Visit. 
For a detailed description of the sequence in which these assessments are administered at 
Screening or Baseline Visit, see Section 9.1.1. 
9.5.1.2 
Efficacy Assessments 
Efficacy assessments are summarized in the following sections.  At the Baseline Visit 
cognition will be assessed by the MoCA, which must be the first clinical scale to be 
administered before any invasive procedures, followed by the WAIS-IV DSC and then the 
CIBIS-Plus.  The caregiver or informant will also complete the CIBIS-Plus, NPI, CFI, 
SAPS-PD, and FAQ.  During the Treatment Period 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 efficacy assessment to be 
administered, followed by the WAIS-IV DSC (after 12 weeks only), then the CIBIC-Plus and 
finally the MMSE (after 12 weeks only).  Whenever possible, a subject should have the same 
rater administering the MoCA and the CIBIC-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 caregiver or informant will also complete the 
CIBIC-Plus, NPI, CFI, SAPS-PD (after 12 weeks only) and FAQ (after 12 weeks only).  The 
caregiver or informant will also complete the CIBIC-Plus, NPI, CFI, SAPS-PD (after 
12 weeks only) and FAQ (after 12 weeks only). 


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For a detailed description of the sequence in which these assessments are administered 
during the Treatment Phase, see Section 9.1.2. 
9.5.1.2.1 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 or PDD.  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 5. 
9.5.1.2.2 WECHSLER ADULT INTELLIGENCE SCALE-4TH EDITION DIGIT SYMBOL CODING 
(WAIS-IV DSC) 
This is the Digit-Symbol Substitution Test from the WAIS-IV.  The test consists of small 
blank squares presented in rows with one of 9 numbers (1-9) randomly printed directly above 
each blank square.  A “key” is printed above the rows of blank squares.  The “key” pairs 
numbers 1 through 9 with an unfamiliar symbol.  Following a short series of practice trials, 
the subject must use the key to fill in the blank squares in order (working from left to right 
across the rows) with the symbol that is paired with the number over the blank square.  The 
subject must work as fast as possible for 120 seconds.  The measure of interest is known as 
the Digit Symbol Coding, which is the number of squares filled in correctly within the time 
limit (maximum score=135).  This test engages multiple cognitive abilities including 
attention, psychomotor speed, complex scanning, visual tracking, and immediate memory.  
Alternate versions will include the identical symbols and digits re-paired. 
The WAIS-IV DSC will be assessed as designated in Table 5. 
9.5.1.2.3 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 postbaseline as part of the given protocol. 
At the 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 the Treatment Period, the rater will administer the CIBIC-Plus separately to the 
subject and the caregiver or informant as designated in Table 5.  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), 


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2 (moderate improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 
6 (moderate worsening), and 7 (marked worsening). 
If during the study, the designated caregiver or informant relinquishes his/her responsibilities 
as caregiver or informant, a replacement caregiver or informant must be found.  If a 
replacement caregiver or informant is found who does not have similar knowledge of the 
subject’s clinical status from Baseline throughout the Treatment Period, then the CIBIC-Plus 
will not be conducted but subject may continue in the study.  If no replacement caregiver or 
informant is available at all the subject must be discontinued from the study. 
9.5.1.2.4 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 also assesses the degree of caregiver or informant distress engendered by each of the 
symptoms (NPI-D).  It is rated from 0 to 144 with high scores meaning a greater 
neuropsychiatric disturbance.  Two subscores will be derived NPI-10 (covering the domains 
of delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, disinhibition, irritability/lability and motor 
disturbance) and NPI-4 (covering the domains of delusions, hallucinations, apathy and 
depression).   
The NPI will be assessed as designated in Table 5.  The caregiver or informant will complete 
the NPI at these visits. 
9.5.1.2.5 SCALE FOR ASSESSMENT OF POSITIVE SYMPTOMS IN PARKINSON’S DISEASE 
(SAPS-PD) 
The SAPS-PD is a structured clinical interview originally designed for use in schizophrenia.  
It includes 5 domains of positive symptoms: hallucinations, delusions, bizarre behavior, 
positive formal thought disorder and inappropriate affect.  The SAPS-PD is adapted from the 
Scale for Assessment of Positive Symptoms (SAPS) and includes items that are reflective of 
the hallucinations and delusions in PDD.  It is a 9-item scale adapted from the hallucinations 
and delusions domains of the SAPS.  There are 5 items for hallucinations (including auditory, 
voices conversing, somatic/tactile, visual and global hallucinations) and 4 items for delusions 
(including persecutory, jealousy, reference and global delusions).  Each item is scored on a 
scale of 0 to 5, with 0 being none and 5 representing severe and frequent symptoms.  
Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting 
greater severity of illness.  The SAPS-PD will be assessed as designated in Table 5.   
9.5.1.2.6 MINI-MENTAL STATE EXAMINATION (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).  The MMSE will be assessed as designated in Table 5. 


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9.5.1.2.7 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 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 5. 
9.5.1.2.8 CLINICIAN GLOBAL IMPRESSION OF CHANGE IN DEMENTIA WITH LEWY BODIES 
(CGIC) 
The CGIC 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, behavior and the impact of the symptoms on the patient’s ability to function) and 
safety data.  The CGIC will be assessed as designated in Table 5. 
9.5.1.2.9 FUNCTIONAL ASSESSMENTS QUESTIONNAIRE (FAQ) 
On the basis of interviews with the caregivers/informants, subjects will be rated for ability to 
carry out ten complex activities of daily living:  (1) manage finances, (2) complete forms, 
(3) shop, (4) perform games of skill or hobbies, (5) prepare hot beverages, (6) prepare 
balanced meal, (7) follow current events, (8) attend to television programs, books, and 
magazines, (9) remember appointments, and (10) travel out of the neighborhood.  Each 
activity will be rated as 0 (normal, does without difficulty), 1 (has difficulty but does by self), 
2 (requires assistance), or 3 (dependent).  Scores will be summed across items to provide a 
total disability score (higher scores = greater impairment; maximum score = 30).  If an 
activity was never or very rarely performed premorbidly, it will be marked as “Not 
Applicable” and will not be included in the score.  A proportional score will be derived for 
subjects who mark any activity as ‘Not Applicable’ as follows (achieved score/(30 – 3 times 
the number of activities marked ‘Not Applicable’).  The FAQ will be assessed as designated 
in Table 5. 
9.5.1.3 
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. 
9.5.1.3.1 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 Weeks 6, 9, and 12:  At predose 
(within 30 minutes before dosing) and 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 


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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 eCRFs.   
CSF samples 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.  Another PK sample will be collected at 
1 to 4 hours postdose. 
Plasma concentrations of E2027 and its metabolite HP4 and CSF concentrations of E2027 
will be measured using validated liquid chromatography with tandem mass spectrometry 
(LC-MS/MS) assay methods. 
9.5.1.3.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS 
Baseline Biomarker Assessments 
A plasma sample will be collected during the Screening Period (Tier 3) to measure 
biomarkers related to AD copathology (including amyloid and p-tau) and other biomarkers 
related to DLB or PDD.  These baseline plasma amyloid Aβ42/Aβ40 ratio will be used to 
classify subjects into the various categories (DLB without amyloid copathology, DLB with 
amyloid copathology, PDD without amyloid copathology and PDD with amyloid 
copathology).  The baseline plasma biomarkers may also be used to define other subgroups 
classifications of subjects for subgroup analyses. 
A CSF sample will be collected during the Screening Period (at least 7 days before the 
Baseline Visit) to measure baseline CSF cGMP and biomarkers related to DLB or PDD.  
These DLB or PDD related biomarkers may be used to define other subgroups classifications 
of subjects for subgroup analyses. 
Plasma concentrations of Aβ42 and Aβ40 will be measured by the validated 
immunoprecipitation LC-MS/MS C2N Preclivity plasma assay.  Plasma concentrations of 
p-tau 181, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) will be 
measured by Quanterix Simoa plasma assay.   
CSF concentrations of cGMP will be measured using a validated assay.  Other CSF 
biomarkers represented by Aβ42, Aβ40, tau, p-tau will be measured by Lumipulse platform 
and CSF NFL, neuregulin (NRG) will be measured by Simoa. 
Pharmacodynamic Assessments 
CSF samples will be collected during the Screening Period (at least 7 days before the 
Baseline Visit) and after 9 weeks on E2027.  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 be collected 
after the predose blood draw for PK and plasma biomarker analysis at the study visit after 


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9 weeks on E2027.  The CSF samples will be assayed for cGMP and E2027.  Other CSF 
biomarkers related to DLB or PDD or E2027 PD effects may also be assayed, if appropriate.  
CSF concentrations of cGMP and other biomarkers will be measured using validated assays. 
A predose plasma sample will be collected at the study visit after 9 weeks on E2027.  It will 
be assayed for plasma biomarkers related to DLB or PDD or E2027 PD effects on these 
biomarkers if appropriate.  Plasma concentrations of Aβ42 and Aβ40 will be measured by the 
validated immunoprecipitation LC-MS/MS C2N Preclivity plasma assay.  Plasma 
concentrations of p-tau 181, GFAP, and NFL will be measured by Quanterix Simoa plasma 
assay. 
Pharmacogenomic Assessments 
Blood samples will be collected as specified in the Schedule of Procedures/Assessments 
(Table 5) 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 
(including apolipoprotein E [ApoE] genotype).  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 or PDD. 
9.5.1.4 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs; regular 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 as detailed in Table 5.  A safety brain MRI may also be performed at 
Unscheduled Visits if deemed appropriate by the investigator. 
9.5.1.4.1 ADVERSE EVENTS 
An 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) 


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• 
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, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase.  
Refer to Section 9.5.4.1 for the time period after the end of treatment for SAE collection.   
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 Adverse Event 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 msec and there is an increase of more than 60 msec from baseline.  Any ECG 
abnormality that the investigator considers as an AE should be reported as such. 
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 9.5.1.4.8 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. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
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 


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The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.4.2 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. 
9.5.1.4.2 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) 
• 
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.  


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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 
9.5.1.4.3 STUDY-SPECIFIC ADVERSE EVENTS 
The study-specific events, fall, syncope, skin rash considered to be related to study drug, AEs 
that may signal drug abuse potential, and a “yes” answer to Type 4 or 5 suicidal ideation, or a 
“yes” response to any suicidal behavior on the C-SSRS, should always be considered adverse 
events and reported on the Adverse Event eCRF and on the event-specific eCRFs designed to 
collect additional information on specific events.  It is the responsibility of the investigator to 
review the results of the C-SSRS and determine if any result constitutes an AE. 
These AEs 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. 
Skin Rash Considered Related to Study Drug 
If a subject develops a skin rash that 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 


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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.  
Adverse Events that May Signal Drug Abuse Potential 
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 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 2 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 2] 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 


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• 
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 
9.5.1.4.4 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study. 
Table 4 
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 
Calcium, 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, cholesterol, globulin, glucose, lactate dehydrogenase, 
phosphorus, total protein, triglycerides, uric acid, TFTa (TSH, free 
triidothyronine, and free thyroxine), vitamin B12a 
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:  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 


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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 9.5.1.4.1 and the eCRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event eCRF 
(see Section 9.5.4.3.2). 
9.5.1.4.5 VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic blood pressure [BP] and diastolic BP [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 5) 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.  
When vital signs are to be obtained on the same day as 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 BP upon standing without lightheadedness) or symptomatic 
orthostatic hypotension (change in BP 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  
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. 
9.5.1.4.6 PHYSICAL EXAMINATIONS 
Complete and brief physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5).  Documentation of the physical examinations will be 


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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. 
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.   
In the brief physical examination, health status will be assessed by brief evaluation of the 
chest (including heart and lungs), abdomen and limbs, and other physical conditions of note.  
The subject must be queried regarding changes in physical status since the last examination. 
9.5.1.4.7 ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of Procedures/ 
Assessments (Table 5).  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 
Section 9.5.1.4.1) and the eCRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF. 
9.5.1.4.8 OTHER SAFETY ASSESSMENTS 
Columbia Suicide Severity Rating Scale (C-SSRS) 
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline 
Visits, every 3 weeks during the Treatment Period, and at the Follow-Up Visit, as designated 
in the Schedule of Procedures/Assessments (Table 5). 
Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III 
(MDS UPDRS-III):  Motor Examination  
The MDS UPDRS 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.  It is recommended that 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). 


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9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Schedule of Procedures/Assessments 
Table 5 presents the schedule of procedures/assessments for the study. 
 


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Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 
Phase 
Pretreatment 
Treatment 
 
 
Period Screening 
Baseline 
Treatment 
Follow-Up (FU) 
Early 
Discontinuation 
(ED)d 
Unschedulede 
Visita 
1b 
2c 
3c 
Telephone 
4 
5 
6 
7 
8  
Day 
-49 to -8 
-7 to -1 
1 
21 
42 
63 
84 
112 
  
  
Weeks Elapsed Since Start of Treatment 
 
 
0 
3 
6 
9 
12 
16 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X (Tier 1) 
 
 
 
 
 
 
 
 
 
Medical history 
X (Tier 1) 
 
 
 
 
 
 
 
 
 
History of DLB or PDD 
X (Tier 1) 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
X (Tier 1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMSE g 
X (Tier 2) 
 
 
 
 
 
X 
 
X 
X 
GDS 
X (Tier 2)f 
 
 
 
 
 
 
 
 
 
MoCAg 
X (Tier 2)f 
X 
 
 
X 
 
X 
 
X 
X 
SFQ 
X (Tier 2)f 
 
 
 
 
 
 
 
 
 
CFI g 
X (Tier 2)f 
X 
 
 
X 
 
X 
 
X 
X 
NPI g 
X (Tier 2)f 
X 
 
 
X 
 
X 
 
X 
X 
CIBIS-Plusg 
 
X 
 
 
 
 
 
 
 
 
CIBIC-Plusg 
 
 
 
 
X 
 
X 
 
X 
X 
WAIS-IV DSC g 
 
X 
 
 
 
 
X 
 
X 
X 
SAPS-PD g 
 
X 
 
 
 
 
X 
 
X 
X 
FAQ g 
 
X 
 
 
 
 
X 
 
X 
X 
CGIC 
 
 
 
 
X 
 
X 
 
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 
Blood for plasma biomarkers 
X (Tier 3) 
 
 
 
 
Xp 
 
 
 
 
Height 
X (Tier 4) 
 
 
 
 
 
 
 
 
 
Weight 
X (Tier 4) 
 
 
 
 
 
X 
 
X 
X 


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Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 
Phase 
Pretreatment 
Treatment 
 
 
Period Screening 
Baseline 
Treatment 
Follow-Up (FU) 
Early 
Discontinuation 
(ED)d 
Unschedulede 
Visita 
1b 
2c 
3c 
Telephone 
4 
5 
6 
7 
8  
Day 
-49 to -8 
-7 to -1 
1 
21 
42 
63 
84 
112 
  
  
Weeks Elapsed Since Start of Treatment 
 
 
0 
3 
6 
9 
12 
16 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X (Tier 4) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination 
X (Tier 4) 
 
 
 
 
 
 
 
 
 
Brief physical examination 
 
X 
 
 
 
 
X 
X 
X 
X 
12-lead ECGi 
X (Tier 4) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood and urine for clinical laboratory testsj 
X (Tier 4 
X j 
 
 
X 
 
X 
 
X 
X 
Blood for vitamin B12 test 
X (Tier 4) 
 
 
 
 
 
 
 
 
 
Blood for thyroid function testsk 
X (Tier 4) 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X (Tier 4) 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy testl 
X (Tier 4) 
 
 
 
 
 
 
 
 
 
Urine pregnancy testl 
 
X 
 
 
 
 
 
 
 
 
Safety brain MRIm 
X (Tier 5) 
 
 
 
 
 
 
 
 
Xm 
DAT brain imaging, MIBG scann 
X (Tier 6) 
 
 
 
 
 
 
 
 
 
CSF sample by LP for PK and PD biomarkerso 
X 
 
 
 
 
X 
 
 
 
 
Plasma sample for PKp 
 
 
 
 
X 
X 
X 
 
X 
X 
PGx sampleq 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start open-label treatment on E2027 50 mg QDc 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
X 
 
X 
X 
X 
 
 
 
 
AE = adverse event, CFI = Cognitive Fluctuation Inventory,  CGIC = Clinician Global Impression of Change, 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, DLB = dementia with Lewy bodies, ECG = electrocardiogram, ED = early discontinuation, FAQ = Functional Assessments 
Questionnaire, FU = follow-up, GDS = Geriatric Depression Scale, HYS = Hoehn and Yahr Scale, INR = international normalized ratio, LP = lumbar puncture, MIBG = 123I-
meta-iodobenzylguanidine, MMSE = Mini-Mental State Examination, MoCA = Montreal Cognitive Assessment, MRI = magnetic resonance imaging, NPI = Neuropsychiatric 
Inventory, PD = pharmacodynamic, PDD = Parkinson’s disease dementia, PGx = pharmacogenomic, PK = pharmacokinetic, PTT = partial thromboplastin time, QD = once 
daily, SAPS-PD = Scale for Assessment of Positive Symptoms in Parkinson’s Disease,  SFQ = Short Fluctuation Questionnaire, UPDRS-III = Unified Parkinson’s Disease 
Rating Scale Part III, WAIS-IV DSC = Weischler Adult Intelligence Scale-4th Edition Digit Symbol Coding 


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Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 
Phase 
Pretreatment 
Treatment 
 
 
Period Screening 
Baseline 
Treatment 
Follow-Up (FU) 
Early 
Discontinuation 
(ED)d 
Unschedulede 
Visita 
1b 
2c 
3c 
Telephone 
4 
5 
6 
7 
8  
Day 
-49 to -8 
-7 to -1 
1 
21 
42 
63 
84 
112 
  
  
Weeks Elapsed Since Start of Treatment 
 
 
0 
3 
6 
9 
12 
16 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
a:  A window of ±4 days will be permitted for Visit 4 to 8 (Follow-Up) inclusive. If under extenuating circumstances (eg, the COVID-19 pandemic), a subject is not able to visit 
the study site for scheduled safety and efficacy assessments, then any assessments not performed during the scheduled visit may be performed remotely (if feasible) with 
sponsor approval. 
b: The Screening Period takes place over a period of up to 6 weeks.  Subjects who complete screening assessments in less than 6 weeks may proceed to the Baseline Period.  At 
Screening, assessments are grouped into tiers and should be performed sequentially.  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.  Subjects will need to 
satisfy the eligibility criteria in each tier before proceeding to the next tier.  Subjects who cannot complete screening within 6 weeks should be discussed with the sponsor for 
extension of the Screening Period by up to 1 week. 
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 and at least 1 week after CSF collection.  After completion of study assessments subjects who are eligible will be 
dispensed with study drug (E2027) 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 information about 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.  At these originally 
scheduled visits that take place after the ED Visit, blood PK samples, plasma biomarker samples, and CSF samples will not be collected. 
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:  Tier 2 screening assessments in subjects should be performed in the following order:  MMSE and GDS first; then MoCA.  The caregivers or informants should complete the 
SFQ, CFI, and NPI.  Subjects who do not meet eligibility criteria on MMSE and GDS should be screen failed and the other assessments do not need to be performed.  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. The caregiver or informant must normally attend in person with the subject.  However, under extenuating circumstances only, and only 
with the approval of the sponsor (eg, during the COVID-19 pandemic), the assessments may be administered remotely via telephone, sponsor-approved telehealth, or home 
visit. 
g:  Visit 2, 5, 7, ED Visit and FU 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, followed by the WAIS-IV DSC (not at Visit 5), then the CIBIS/CIBIC-Plus and finally the MMSE (not at Visit 5).  The caregiver or informant 
will also complete the CIBIS/CIBIC-Plus, NPI, CFI, SAPS-PD (not at Visit 5) and FAQ (not at Visit 5).  The caregiver or informant must normally attend in person with the 
subject.  The CIBIS-Plus and CIBIC-Plus should be performed by an independent rater from other scales.  Efficacy assessments should be completed before more invasive 


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Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 
Phase 
Pretreatment 
Treatment 
 
 
Period Screening 
Baseline 
Treatment 
Follow-Up (FU) 
Early 
Discontinuation 
(ED)d 
Unschedulede 
Visita 
1b 
2c 
3c 
Telephone 
4 
5 
6 
7 
8  
Day 
-49 to -8 
-7 to -1 
1 
21 
42 
63 
84 
112 
  
  
Weeks Elapsed Since Start of Treatment 
 
 
0 
3 
6 
9 
12 
16 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
procedures (eg, physical examination, ECG, blood draws) unless otherwise specified.  At Visits 5, 7 and ED Visit the MoCA should be the first clinical scale to be 
administered postdose and before the first postdose PK sample.  At Visits 5, 7, and ED Visit the investigator should complete the CGIC after reviewing all the subject’s 
efficacy endpoints. The caregiver or informant must normally attend in person with the subject.  However, under extenuating circumstances only, and only with the approval 
of the sponsor (eg, during the COVID-19 pandemic), the assessments may be administered remotely via telephone, sponsor-approved telehealth, or home visit.   
h:  Single measurements of vital signs will be performed after the 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.  For the visits at which PK sampling is also scheduled 
(ie, Week 6 [Visit 5], Week 9 [Visit 6], and Week 12 [Visit 7], or ED Visit) vital signs will be taken at 1 – 4 hours postdose, before PK sampling.  
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 all subjects clotting screen (prothrombin time, PTT, INR) will 
also be performed only at the Screening Visit with the other clinical laboratory tests.  
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 days before CSF collection.  The rules regarding when DAT brain imaging or MIBG scan will be performed are specified in Inclusion Criterion 2.  
o:  CSF will be collected by LP in all subjects.  During Screening CSF may be collected at any time after completion of screening procedures and a subject is deemed eligible, 
at least 1 week after DAT or MIBG imaging and at least 1 week before Visit 2.  CSF will be collected again at Visit 6. 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 6) 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 as per local guidelines.  At Week 9 (Visit 6), a predose blood sample for PK and a blood sample 
for plasma biomarkers 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 6 
occurs after an ED Visit, blood PK samples, plasma biomarker sample 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 - 4 hours postdose at Week 6 (Visit 5) and Week 12 
(Visit 7) (or ED Visit).  At Week 6 (Visit 5) and Week 12 (Visit 7) (or ED Visit) study drug will be administered before efficacy assessments are performed.  A predose PK 
sample and a blood sample for plasma biomarkers will be collected at Week 9 (Visit 6), followed by CSF collection.  The subject will then be dosed with study drug and a 


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Table 5 
Schedule of Procedures/Assessments in Study E2027-A001-203 
Phase 
Pretreatment 
Treatment 
 
 
Period Screening 
Baseline 
Treatment 
Follow-Up (FU) 
Early 
Discontinuation 
(ED)d 
Unschedulede 
Visita 
1b 
2c 
3c 
Telephone 
4 
5 
6 
7 
8  
Day 
-49 to -8 
-7 to -1 
1 
21 
42 
63 
84 
112 
  
  
Weeks Elapsed Since Start of Treatment 
 
 
0 
3 
6 
9 
12 
16 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
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, plasma biomarker sample and CSF samples will not be collected.  
q:  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 5 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 6 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 6 
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 
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, β-hCG 
1 
1 × 2.5 
None 
None 
2.5 
Hematology 
4 
1 × 2.0 
1 × 2.0 
2 × 2.0 
8.0 
INR, prothrombin time, PTT 
1 
1 × 2.0 
None 
None 
2.0 
PD (biomarkers) 
2 
1 × 6.0 
None 
1 × 6.0 
12.0 
PK 
6 
None 
None 
6 × 6.0 
36.0 
PGx 
1 
None 
1 × 6.0 
None 
6.0 
Total blood volume to be collected 
16.3 
10.5 
51.0 
77.8 
CSF 
PK and PD 
2 
1 × 7.0 
None 
1 × 7.0 
14.0 
Total CSF volume to be collected 
7.0 
None 
7.0 
14.0 
β-hCG = beta-human chorionic gonadotropin, CSF = cerebrospinal fluid, INR = international normalized 
ratio, PD = pharmacodynamic, 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.  
 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of LBD and 
other forms of dementia.  The primary endpoint is the percentage change from baseline of 
CSF cGMP, which is the main PD response to E2027 that may show different responses in 
subjects with and without amyloid copathology.  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, 


 
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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. 
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase.  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 relevant follow-up information received on SAEs should be forwarded within 24 hours 
of its receipt.  If the relevant 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. 
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 partner’s pregnancy of a male 
subject in which the estimated date of conception is either before the last visit or within 


 
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98 days of last study treatment), 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, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus 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 24 hours 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 24 hours 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.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event 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 
and Intentional Overdose, even if asymptomatic, are always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 


 
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criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event eCRF. 
9.5.4.3.2 REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST 
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1).  If the event 
does not meet serious criteria, the seriousness criteria on the SAE form should be indicated as 
“nonserious.”   
• 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory 
value that is greater than or equal to 3× the upper limit of normal (ULN) 
AND 
• 
Elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN  
AND AT THE SAME TIME 
• 
Alkaline phosphatase lab value that is less than 2× the ULN 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve. 
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 
Not applicable. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 


 
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9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 5). 
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, pregnancy, withdrawal of consent, 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.   
If any of the subgroups have fewer than 6 subjects completing at least 9 weeks of treatment 
and the posttreatment CSF sample, then further subjects may be screened and treated with 
E2027. 
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 
subject should be discontinued, except for specific situations described below.   
Skin Rash 
As already described in Section 9.5.1.4.3, 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: 
• 
A bullous rash regardless of severity  
• 
A moderate to severe nonbullous rash  
As already described in Section 9.5.1.4.3, 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  
• 
A moderate to severe nonbullous rash  


 
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Prolongation of QTcF Interval on ECG 
Subjects who have mean QTcF on triplicate ECG >500 msec should be discontinued.   
Use of Prohibited Medications 
As per Section 9.4.7.2, subjects who start treatment with any of the following medications 
during the study will be discontinued due to the risk of PK or PD interactions: 
• 
Drugs known to be strong inhibitors of CYP3A, grapefruit juice, and grapefruit products 
• 
Drugs known to be moderate to strong inducers of CYP3A 
• 
Drugs known to cause prolongation of the QT interval, including but not limited to drugs 
that may cause cardiac arrhythmias 
• 
Drugs that are phosphodiesterase inhibitors (eg, theophylline, aminophylline, sildenafil, 
tadalafil, vardenafil, dipyridamole, roflumilast, apremilast, inamrinone, milrinone, and 
enoximone)   
As per Section 9.4.7.2, subjects who start treatment with any of the following medications 
during the study will be discontinued due to interference with efficacy assessments or safety: 
• 
Anticholinergic drugs that have CNS activity 
• 
Pimavanserin 
• 
Subjects who 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 of treatment, will not undertake the 
2nd CSF collection but may continue in the study.  However, they will not be considered 
as completers of the study. 
Decline to Loss of Capacity to Consent 
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. 
Contraception Requirement 
Subjects who are in the treatment period and who meet the criteria that requires them (and 
the female partners of male subjects) to practice contraception as specified in Section 9.3.2, 
but who cannot comply or are unwilling to do so, will be discontinued from study drug.   
9.5.6 
Abuse or Diversion of Study Drug 
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug eCRF. 
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.4.1.  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, 
standard operating procedures, 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 eCRF 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 eCRF 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 or Investigator and Site Information Form 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. 


 
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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.  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 SAP, which will be finalized before 
database lock. 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.   
9.7.1.1 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINT 
• 
Percentage change from baseline in CSF cGMP at 9 weeks of treatment.   
9.7.1.1.2 SECONDARY ENDPOINTS 
• 
Safety and tolerability of E2027 as measured by the following: 
- 
Incidence of adverse events including severe AEs, serious AEs, AEs resulting in 
discontinuation   
- 
Incidence of orthostatic hypotension and orthostatic tachycardia   
- 
Incidence of markedly abnormal laboratory values and shifts from baseline of 
laboratory values   
- 
Incidence of abnormal ECG parameters and abnormal ECG findings   
- 
Incidence of suicidality based on C-SSRS   
- 
Changes from baseline in the total score of UPDRS-III  
9.7.1.1.3 EXPLORATORY ENDPOINTS  
• 
The following clinical efficacy endpoints at 12 weeks of treatment 
- 
Change from baseline in MoCA total score 
- 
Change from baseline in WAIS-IV DSC score 
- 
CIBIC-Plus scale 
- 
CGIC scale 
- 
Change from baseline in CFI score 
- 
Change from baseline in MMSE total score 
- 
Change from baseline in NPI total score, subscores and caregiver distress score 
- 
Change from baseline in SAPS-PD total score 
- 
Change from baseline in FAQ total score 
• 
Change from baseline in CSF cGMP at 9 weeks of treatment 


 
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• 
Percentage change and change from baseline at 9 weeks of treatment in other biomarkers 
in CSF and/or plasma, including using other diagnostic subgroups classifications based 
on baseline biomarkers (if appropriate) 
• 
PK of E2027 in subjects with DLB or PDD, using population modelling 
• 
Relationships between E2027 in plasma/CSF and its effects on the following variables  
using PK/PD modelling, if data permit: 
- 
Plasma/CSF PD biomarkers (including CSF cGMP),  
- 
Clinical efficacy (including MoCA, WAIS-IV DSC, CIBIC-Plus, NPI, MMSE, CFI, 
SAPS-PD, FAQ, and CGIC at 12 weeks of treatment),  
- 
Safety variables 
• 
Relationships of the plasma and CSF PD biomarkers compared to MoCA, WAIS-IV 
DSC, CIBIC-Plus, NPI, MMSE, CFI, SAPS-PD, FAQ, and CGIC at 12 weeks of 
treatment, if data permit 
• 
Relationships amongst plasma biomarkers and CSF biomarkers at baseline and after 
treatment (if appropriate)  
• 
Subgroup analyses based on genotype classification for CSF cGMP changes from 
baseline and clinical endpoints 
9.7.1.2 
Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 post baseline safety assessment. 
The Full Analysis Set (FAS) is the group of subjects who receive at least 1 dose of study 
drug and have baseline and at least 1 post baseline MoCA measurement. 
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 
1 PD parameter. 
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 subjects enrolled by each site will be 
summarized by subgroup and overall.   
Study Completion:  The number (percent) of 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 
subgroup and total for all subjects.  
Completion of Study Treatment:  The number (percent) of treated subjects who completed 
study drug and who discontinued from study drug will be summarized according to the 
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discontinuation, based on data reported on Early Discontinuation from Study Drug eCRF.  
The number (percent) will be presented by subgroup and total for all subjects.  Subjects who 
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 subgroup and overall 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). 
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 2020).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by subgroup and overall, 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 exploratory efficacy endpoints will be summarized based on the FAS, by subject 
subgroup (DLB without amyloid copathology, DLB with amyloid copathology, PDD without 
amyloid copathology, and PDD with amyloid copathology). 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
The Safety Analysis Set will be used for E2027 concentration listings and for summaries of 
E2027 concentrations in plasma and CSF by dose and day.   
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 and 
2 studies.  As appropriate, the effect of covariates on the PK of E2027, such as baseline 
characteristics/demographics will be evaluated.  Derived exposure parameters such as steady 
state area under the concentration time curve or average concentration of E2027 and other 
derived parameters may be calculated from the final PK model using the individual posterior 
estimates of the PK parameters and dosing history.  The details will be described in the 


 
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separately prepared analysis plan and its report, and the results will not be included in the 
clinical study report. 
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 and plasma PD 
biomarkers.  The percentage change from baseline in CSF cGMP at 9 weeks of treatment will 
be analyzed to compare different subject subgroups (DLB without amyloid copathology vs 
DLB with amyloid copathology, and PDD without amyloid copathology versus PDD with 
amyloid copathology).  Analyses, comparing the different subgroups, of the percentage 
change from baseline in CSF cGMP will be performed using an analysis of covariance, 
where baseline CSF cGMP will be included as a covariate.  The least square (LS) means, 
LS mean subgroup differences and 95% CIs will be presented. 
The change from baseline in CSF cGMP at 9 weeks of treatment will also be analyzed.  
Other CSF and plasma PD biomarkers may be analyzed similarly, if appropriate. 
The CSF and plasma PD biomarkers will be summarized by subject subgroups, as 
appropriate.  Summaries and figures will be produced exploring the relationships between 
CSF and plasma PD biomarkers and the efficacy endpoints. 
Pharmacodynamic/Pharmacokinetic Analyses 
The correlation amongst plasma and CSF exposure to E2027 and the various efficacy and 
biomarker endpoints will be explored graphically.  The details will be described in the 
separately prepared analysis plan and its report, and the results will not be included in the 
clinical study report. 
Pharmacogenomic Analyses 
The percentage change in CSF cGMP at 9 weeks, change in CSF cGMP at 9 weeks and other 
CSF and plasma PD biomarkers will be summarized by ApoE4 status, using the PD Analysis 
Set.  Other PGx data will be summarized similarly.   
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 subgroup and overall. 
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 


 
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category will be presented by subgroup and overall.  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 subgroup and overall.  Overall exposure (number of 
subject-weeks) is defined as summation over all subjects’ exposure durations and will be 
summarized by subgroup and overall. 
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 22.0 or higher) lower 
level term 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 during treatment, having been absent at 
pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that 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 subgroup and overall.  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 
(Yes [related] and No [not related]). 
The number (percentage) of subjects with treatment-related TEAEs, treatment-emergent 
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. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) 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 


 
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also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period. 
Appendix 3 (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 subgroup and overall. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and subgroup and overall.  ECG interpretation (categorized as normal; abnormal, not 
clinically significant; and abnormal, clinically significant) will be presented by visit and 
subgroup and overall using frequency count.  The number (percentage) of subjects with 
postbaseline abnormal ECG result in QTcF will be summarized by subgroup and overall. 
9.7.1.8.6 OTHER SAFETY ANALYSES 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS responses will be mapped to the Columbia-classification algorithm of suicide 
assessment (C-CASA).  The incidence of suicidal ideation or suicidal behavior will be 
summarized by subgroup and overall.  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. 
Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III 
(MDS UPDRS-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 subgroup and overall. 
9.7.2 
Determination of Sample Size 
Assuming the standard deviation of percentage change from baseline in CSF cGMP at 
Week 9 is 60, the sample size of 6 completers per group (for 8 enrolled subjects per arm, 
assuming a 25% dropout rate), will have approximately 80% power to detect the difference 
in change from baseline of CSF cGMP of 100% between the DLB without amyloid 
copathology subgroup and the DLB with amyloid copathology subgroup.  The analysis 


 
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between the PDD without amyloid copathology subgroup and the PDD with amyloid 
copathology subgroup, also has approximately 80% power to detect the difference in change 
from baseline of CSF cGMP of 100% (same assumptions as above).  These sample size 
calculations illustrate the possible differences that could be seen between subgroups.  
However, without previous data on the differences between subgroups in CSF cGMP, these 
are for illustration only and it is not expected statistical significance will be reached with 
6 subjects per subgroup. 
The probability of observing a difference in percentage of CSF cGMP between 2 subgroups 
(DLB without amyloid copathology subgroup minus DLB with amyloid copathology 
subgroup, or PDD without amyloid copathology subgroup minus PDD with amyloid 
copathology subgroup) ≥30% depends on the true difference between the 2 groups.  If the 
true difference is 100%, there will be 97.8% probability that the observed difference is 
≥30%.  If the true difference is 60%, the probability is 80.7%.  If the true difference is 10%, 
there will be 28.2% probability that the observed difference is ≥30%. 
9.7.3 
Interim Analysis 
No interim analysis will be conducted. 
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. 
10 REFERENCE LIST 
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placebo-controlled, multicentre trial. Lancet Neurol. 2009;8:613–8. 
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;74:1215-20. 
Biundo R, Wies L, Bostantjopoulou S, Stefanova E, Falup-Percurariu C, Kramberger MG, et 
al.  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. 
Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer’s disease. Nature 
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Doecke JD, Pérez-Grijalba V, Fandos N, Fowler C, Villemagne VL, Masters CL, et al. Total 
Aβ 42/Aβ 40 ratio in plasma predicts amyloid-PET status, independent of clinical AD 
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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. 
Ferman TJ, Aoki N, Boeve BF, Aakre JA, Kantarci K, Graff-Radford J, et al. Subtypes of 
dementia with Lewy bodies are associated with α-synuclein and tau distribution. Neurol. 
2020;95:e155-e165. 
Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, et al. Neuropathological 
and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective 
analysis. Lancet Neurol. 2017;16:55–65. 
Matsunaga S, Kishi T, Yasue I, Iwata N.  Cholinesterase Inhibitors for Lewy Body 
Disorders:  A Meta-Analysis.  Int J Neuropsychopharm. 2015;1–15. 
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.  Neurol. 2017;89:88-100. 
Monfort P, Felipo V. Amyloid impairs, and ibuprofen restores, the cGMP pathway, synaptic 
expression of AMPA receptors and long-term potentiation in the hippocampus. J Alzheimer’s 
Disease. 2010;22:795–809. 
Nedelska Z, Ferman TJ, Boeve BF, Przybleski SA, Lasnick TL, Murray ME, et al. Pattern of 
brain atrophy rates in autopsy-confirmed dementia with Lewy bodies. Neurobiol Aging. 
2015;36(1):452–61. 
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.  Mov Disord. 
2004;19(1):60-7. 
Park L, Hochrainer K, Hattor Y, Ahn SJ, Anfray A, Wang G, et al. Tau induces PSD95–
neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration. 
Nature Neurosci. 2020;23:1079–89. | 
Petrou M, Dwamena BA, Foerster BR, MacEachern MP, Bohnen NI, Muller M, et al. 
Amyloid deposition in Parkinson Disease and Cognitive Impairment: A Systematic Review. 
Mov Disord. 2015;30(7):928–35. 
Walker Z, Possin KL, Boeve BF, Aarsland D.  Lewy body dementias.  Lancet. 
2015;386:1683-97. 


 
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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 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 x-rays, and other imaging reports 
(eg, sonograms, CT scans, MRI, 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 Patient-Reported Outcome (eCOA) 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 eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs. 
Efficacy or safety assessments are evaluated based on the data entered into eCOA.  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 eCRF are to be considered source data: 
• 
Reasons for discontinuation of study treatment 
• 
Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome) 


 
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• 
Reasons for dose modification 
• 
Indication for prior/concomitant medication 
• 
Sampling times for drug concentrations 
• 
Sampling times for clinical laboratory tests 
The data collected by eCOA 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 eCRFs, 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 15 years following the 
completion of the study. 
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 
standard operating procedures 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 
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 


 
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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 


 
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sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


 
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12 APPENDICES 
 


 
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Appendix 1 
Diagnostic Criteria for Probable Dementia With Lewy 
Bodies and Probable Parkinson’s Disease Dementia 
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. 
• 
Rapid eye movement (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.  
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 (DAT) in the basal ganglia on DAT brain scan 
• 
Abnormal (low uptake) in meta-iodobenzylguanidine (MIBG) cardiac scan 
• 
Polysomnography (PSG) confirmation of REM sleep without atonia 
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.   


 
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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. 
The diagnosis of probable Parkinson’s disease dementia (PDD) require the following: 
• 
Diagnosis of Parkinson’s disease according to Queen Square Brain Bank criteria. 
• 
Dementia developing in the context of established Parkinson’s disease (ie, dementia onset 
>12 months after onset of Parkinson’s disease) with cognitive impairment in more than 
one domain and severe enough to impair daily life. 
• 
Impairment in at least 2 of the 4 cognitive domains below: 
- 
Attention, which may fluctuate 
- 
Executive function 
- 
Visuospatial function 
- 
Memory (in the form of free recall, which may improve with cueing) 
• 
Behavioral features listed below support the diagnosis but absence of such features does 
not exclude the diagnosis: 
- 
Apathy 
- 
Depression 
- 
Anxiety 
- 
Hallucinations 
- 
Delusions 
- 
Excessive daytime sleepiness 
• 
Diagnosis of PDD cannot be made if any of the following criteria are met:  
- 
Cognitive and behavioral symptoms appear solely in the context of other conditions 
such as systemic diseases, drug intoxication or major depression. 
- 
Patient meets criteria for probable vascular dementia 
For assessment for cognitive function, the investigator should take into account scores of the 
MMSE and MoCA used at screening. 
In evaluation of the clinical features, the investigator should take into account the scores in 
the SFQ, CFI, and NPI for cognitive fluctuation, behavioral and neuropsychiatric symptoms. 
 


 
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Appendix 2 
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 
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 


 
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Examples of Adverse Events That May Signal Drug Abuse Potential 
Categories 
Examplesa 
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 
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:  US 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 electronic Case Report Form 
Completion Guidelines.   
b:  Only for events observed within the first 4 weeks of last dose of study drug. 
 


 
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Appendix 3 
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 – 2.5×ULN if 
baseline was normal; 
2.0 – 2.5×baseline if 
baseline was abnormal 
>2.5 – 5.0×ULN if 
baseline was normal; 
>2.5 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
ALT 
>ULN – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 5.0×ULN if 
baseline was normal; 
3.0 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
AST 
>ULN – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 5.0×ULN if 
baseline was normal; 
3.0 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN if 
baseline was normal; 
1.0 – 1.5×baseline if 
baseline was abnormal 
>1.5 – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 10.0×ULN if 
baseline was normal; 
3.0 – 10.0×baseline if 
baseline was abnormal 
>10.0×ULN if 
baseline was normal; 
>10.0×baseline if 
baseline was 
abnormal 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium <LLN 
- 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium <1.0 - 
0.9 mmol/L; 
symptomatic 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium <0.9 - 
0.8 mmol/L; 
hospitalization 
indicated 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium 
<0.8 mmol/L; life-
threatening 
consequences 


 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium >ULN 
- 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium >1.5 - 
1.6 mmol/L; 
symptomatic 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium >1.6 - 
1.8 mmol/L; 
hospitalization 
indicated 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences 
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×baseline; 
>1.5 – 3.0×ULN 
>3.0×baseline; 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 2.5×ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal 
>2.5 – 5.0×ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Glucose, serum-high (hyperglycemia) 
Abnormal glucose 
above baseline with no 
medical intervention 
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes 
Insulin therapy 
initiated; hospitalization 
indicated 
 
life-threatening 
consequences; urgent 
intervention indicated 
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)  
Laboratory finding 
only and intervention 
not indicated 
Oral replacement 
therapy indicated 
 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated 
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; 
intervention initiated 
>155 – 160 mmol/L 
hospitalization 
indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
125-129 mmol/L and 
asymptomatic 
<125 – 129 mmol/L 
symptomatic; 
120 - 124 mmol/L 
regardless of symptoms 
<120 mmol/L 
life-threatening 
consequences 


 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 without 
physiologic 
consequences  
N/A 
>ULN with physiologic 
consequences  
  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = gamma-glutamyl transferase, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.   
 


 
Clinical Study Protocol 
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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E2027-A001-203 
Study Protocol Title: 
An Open-Label Study to Evaluate the Pharmacodynamic 
Effects, Efficacy, Safety, and Tolerability of E2027 in Subjects 
With Dementia With Lewy Bodies or Parkinson’s Disease 
Dementia With or Without Amyloid Copathology 
Investigational Product 
Name: 
E2027 
IND Number: 
123614 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
 
  
 
Neurology Business Group, Eisai Ltd. 
 
Date 
 
 
 
 
 
 
 
 
Neurology Business Group, Eisai Inc 
 
Date 
 
 
 
 
 
 
 
 
Neurology Business Group, Eisai Inc 
 
Date 
 
 
 
 
 
 
 
  
Neurology Business Unit, Eisai Ltd. 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E2027-A001-203 
Study Protocol Title: 
An Open-Label Study to Evaluate the Pharmacodynamic 
Effects, Efficacy, Safety, and Tolerability of E2027 in Subjects 
With Dementia With Lewy Bodies or Parkinson’s Disease 
Dementia With or Without Amyloid Copathology 
Investigational Product 
Name: 
E2027 
IND Number: 
123614 
 
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 Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
<Name of institution> 
Medical Institution 
 
<Name, degree(s)> 
  
  
Investigator 
 Signature 
 Date 
. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2027-A001-203 
Study Protocol 
Title: 
An Open-Label Study To Evaluate the Pharmacodynamic Effects, 
Efficacy, Safety, and Tolerability of E2027 in Subjects With 
Dementia With Lewy Bodies or Parkinson’s Disease Dementia With 
or Without Amyloid Copathology 
Date: 
10 February 2022 
Version: 
Final Version 2.0 


Statistical Analysis Plan 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ............................................................................................... 2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 4 
3 
INTRODUCTION ......................................................................................................... 8 
3.1 
Study Objectives .................................................................................................. 8 
3.1.1 
Primary Objective ...................................................................................... 8 
3.1.2 
Secondary Objective ................................................................................... 8 
3.1.3 
Exploratory Objectives ............................................................................... 8 
3.2 
Overall Study Design and Plan ............................................................................. 9 
4 
DETERMINATION OF SAMPLE SIZE ..................................................................... 11 
5 
STATISTICAL METHODS ........................................................................................ 11 
5.1 
Study Endpoints ................................................................................................. 11 
5.1.1 
Primary Endpoint ..................................................................................... 11 
5.1.2 
Secondary Endpoints ................................................................................ 11 
5.1.3 
Exploratory Endpoints .............................................................................. 12 
5.2 
Study Subjects ................................................................................................... 13 
5.2.1 
Definitions of Analysis Sets...................................................................... 13 
5.2.2 
Subject Disposition................................................................................... 13 
5.2.3 
Protocol Deviations .................................................................................. 13 
5.2.4 
Demographic and Other Baseline Characteristics ...................................... 14 
5.2.5 
Prior and Concomitant Therapy ................................................................ 15 
5.2.6 
Treatment Compliance ............................................................................. 16 
5.3 
Data Analysis General Considerations................................................................ 16 
5.3.1 
Pooling of Centers .................................................................................... 16 
5.3.2 
Adjustments for Covariates ...................................................................... 16 
5.3.3 
Multiple Comparisons/Multiplicity ........................................................... 16 
5.3.4 
Examination of Subgroups........................................................................ 16 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .................................... 17 
5.3.5.1 
Efficacy .......................................................................................... 17 
5.3.5.2 
Safety ............................................................................................. 17 
5.3.6 
Other Considerations ................................................................................ 17 
5.4 
Efficacy Analyses .............................................................................................. 18 
5.4.1 
Primary Efficacy Analyses ....................................................................... 18 
5.4.2 
Secondary Efficacy Analyses ................................................................... 18 
5.4.3 
Other Efficacy Analyses ........................................................................... 18 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ........................................................................................... 18 


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5.5.1 
Pharmacokinetic Analyses ........................................................................ 18 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses .... 18 
5.6 
Safety Analyses.................................................................................................. 20 
5.6.1 
Extent of Exposure ................................................................................... 20 
5.6.2 
Adverse Events......................................................................................... 20 
5.6.3 
Laboratory Values .................................................................................... 21 
5.6.4 
Vital Signs................................................................................................ 22 
5.6.5 
Electrocardiograms ................................................................................... 23 
5.6.6 
Other Safety Analyses .............................................................................. 24 
5.6.6.1 
C-SSRS .......................................................................................... 24 
5.6.6.2 
MDS-UPDRS-III ............................................................................ 24 
5.7 
Other Analyses................................................................................................... 25 
5.8 
Exploratory Analyses ......................................................................................... 25 
6 
INTERIM ANALYSES ............................................................................................... 25 
7 
CHANGES IN THE PLANNED ANALYSES ............................................................ 25 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ............................. 25 
8.1 
Efficacy data handling ........................................................................................ 25 
8.1.1 
Pretreatment/Baseline Efficacy ................................................................. 25 
8.1.2 
Treatment Duration for Efficacy Analyses ................................................ 25 
8.1.3 
Efficacy Data Collected After the ED Visit............................................... 26 
8.2 
PD data handling ................................................................................................ 26 
8.2.1 
Pretreatment/Baseline PD ......................................................................... 26 
8.2.2 
Treatment Duration for PD Analyses ........................................................ 26 
8.2.3 
Duplicate PD Tests ................................................................................... 27 
8.3 
Safety data handling ........................................................................................... 27 
8.3.1 
Baseline Safety ......................................................................................... 27 
8.3.2 
Treatment Duration for Safety Analyses ................................................... 27 
8.3.3 
Handling of Replicate Data ....................................................................... 29 
8.3.4 
Safety Data Collected After the ED Visit .................................................. 29 
8.4 
Algorithms for Efficacy Parameters ................................................................... 29 
8.5 
Algorithms for Safety Parameters ....................................................................... 32 
9 
PROGRAMMING SPECIFICATIONS ....................................................................... 33 
10 STATISTICAL SOFTWARE ...................................................................................... 33 
11 MOCK TABLES, LISTINGS, AND GRAPHS............................................................ 33 
12 REFERENCES ............................................................................................................ 33 
13 APPENDICES ............................................................................................................. 34 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results ..... 34 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AChEI 
acetylcholinesterase inhibitor 
AE 
adverse event 
ATC 
anatomical therapeutic class 
BMI 
body mass index 
BP  
Blood pressure 
C-CASA 
Columbia Classification Algorithm for Suicide Assessment 
CI 
confidence interval 
CIBIC-Plus 
Clinician’s Interview Based Impression of Change Plus Caregiver 
Input 
CFI 
Cognitive Fluctuation Inventory 
CGIC 
Clinician Global Impression of Change 
cGMP 
cyclic guanosine monophosphate 
CRF 
case report form 
CSF cGMP 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS   
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
DBP 
Diastolic blood pressure 
DLB 
Dementia in Lewy Bodies 
ED 
Early Discontinuation 
FAQ 
Functional Assessments Questionnaire 
FAS 
full analysis set 
LLT 
lower level term 
LS 
least squares 
MDS 
Movement Disorders Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
NPI 
Neuropsychiatric Inventory 


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Abbreviation 
Term 
NPI-D 
Neuropsychiatric Inventory – Distress symptoms 
PD 
pharmacodynamic 
PDD 
Parkinson’s Disease Dementia 
PK 
pharmacokinetic 
PT 
Preferred term 
QTcB 
corrected QT interval calculated using Bazett’s formula 
QTcF 
corrected QT interval calculated using Fridericia’s formula 
RBD 
REM sleep behavior disorder 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAPS-PD 
Scale for Assessment of Positive Symptoms in Parkinson’s 
Disease 
SBP 
Supine blood pressure 
SE 
standard error  
SI 
Système International 
SOC 
System organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TLG 
tables, listings, and graphs 
UPDRS-III 
Unified Parkinson’s Disease Rating Scale Part III:  Motor 
Examination 
WAIS-IV DSC 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol 
Coding 
WHO 
World Health Organization 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


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Table 1 Summary of Changes (Version 2) 
Changes in Version 2 
Rationale 
5.2.1 Definitions of Analysis Sets 
Addition to the definition of subjects being 
excluded from the PD Analysis Set, based 
on low drug compliance/PK concentrations 
at Week 9. 
Subjects with low PK concentrations, and 
therefore low drug compliance at Week 9 
had outlying cGMP percentage change 
from baseline values.  This was not helpful 
in determining proof of concept and hence 
they are to be excluded from the PD 
Analysis Set, and kept in all other analysis 
sets.  
5.2.4 Demographic and Other Baseline 
Characteristics and 5.3.4 Examination of 
Subgroups 
Update to cutpoint for CSF Aβ42/40 ratio 
and CSF p-tau181/Aβ(1-42) ratio  
In correct cutpoints were referenced.  CSF 
Aβ42/40 ratio was changed from 0.0597 to 
0.0571. CSF p-tau181/Aβ(1-42) ratio was 
changed from 0.0749 to 0.083.  
5.3.4 Examination of Subgroups and 5.6.2 
Adverse Events 
Removal of subgroups for: On AChEI at 
baseline (Yes or No), Hoehn & Yahr stage 
(0&I&II or III), Baseline MMSE subgroup 
(>14 total score <19, >20 total score <26), 
Age (<65, ≥ 65), NPI hallucination sub-
item 
score 
(≥median/<median), 
Caregiver’s time per week to spend with 
subject (≥median/<median). 
Due to the number of subjects, it was not 
useful to subgroup the data in this detail.  
8.2.3 Duplicate PD Tests 
Wording added to implement derivation 
for any duplicate PD tests received. 
Added for completion for derivation of a 
sigle value if duplicate tests received. 
8.3.2 Treatment Duration for Safety 
Analyses  
Footnote d added to Table 5 
Footnote d added for clarity. 
8.4 Algorithms for Efficacy Parameters 
NPI total scores are set to zero if any part 
To be consistent with the derivation from 
Study 201 


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is missing, changed from set to missing if 
any part is missing. 
 


Statistical Analysis Plan 
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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 for Eisai E2027-A001-203. 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of the study is to demonstrate the Pharmacodynamic (PD) effects of 
E2027 on cerebrospinal fluid (CSF) cyclic guanosine monophosphate (cGMP) in subjects 
with dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) with and 
without amyloid copathology after 9 weeks of treatment. 
3.1.2 
Secondary Objective 
The secondary objective of the study is to evaluate the safety and tolerability of E2027 in 
subjects with DLB and PDD. 
3.1.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate the efficacy of E2027 on the following endpoints after 12 weeks of 
treatment: 
- 
Montreal Cognitive Assessment (MoCA) 
- 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol Coding (WAIS-IV DSC) 
- 
Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) 
- 
Clinician Global Impression of Change (CGIC) 
- 
Cognitive Fluctuation Inventory (CFI) 
- 
Mini-Mental State Examination (MMSE) 
- 
Neuropsychiatric Inventory (NPI) 
- 
Scale for Assessment of Positive Symptoms in Parkinson’s Disease (SAPS-PD) 
- 
Functional Assessments Questionnaire (FAQ) 
• To explore the indirect PD effects of E2027 on plasma biomarkers and CSF biomarkers 
related to DLB and PDD 
• To explore the effects of E2027 on CSF cGMP, other plasma and CSF biomarkers, and 
clinical endpoints using other diagnostic subgroups classifications based on baseline 
biomarkers  
• To characterize the population pharmacokinetics (PK) of E2027 in subjects with DLB or 
PDD, including evaluation of the effects of intrinsic and extrinsic factors on the PK 


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• To explore the relationships amongst the PK exposure of E2027 in plasma/CSF and its 
effects on plasma/CSF biomarkers (including CSF cGMP) as well as clinical efficacy and 
safety endpoints  
• To explore the relationship amongst plasma and CSF biomarkers at baseline and after 
treatment with E2027  
• To collect genomic samples for exploratory investigation on heterogeneity in 
drug-response and clinical features of disease. 
3.2 
Overall Study Design and Plan 
This is a multicenter, open-label study in subjects with DLB or PDD who were treated with 
E2027 for 12 weeks.  Four subgroups of subjects were enrolled as follows:  DLB without 
amyloid copathology, DLB with amyloid copathology, PDD without amyloid copathology, 
and PDD with amyloid copathology.  The presence of amyloid copathology was defined as 
ratio of plasma concentration of Aβ42/Aβ40 <0.092 (based on the C2N PreclivityAD assay).   
The study design allowed for add-on therapy of E2027 to standard of care for DLB and PDD, 
which includes acetylcholinesterase inhibitors (AChEI) and/or memantine at stable doses, 
except for any prohibited medications specified in this protocol.  Subjects who were not 
receiving AChEI or memantine were also eligible to participate in this study but were not 
permitted to start such medications during the study.  It was required that in each subgroup 
there was to be at least 1 subject who was not receiving AChEI or memantine during the 
study.  Subjects were required to be on stable doses of medications prescribed for the 
treatment of Parkinson’s disease, maintained without change during the study. 
For all subjects, study participation comprised 2 phases:  Pretreatment Phase and Treatment 
Phase.  The Pretreatment Phase included a Screening Period and a Baseline Period.  The 
Treatment Phase included a Treatment Period and Follow-up Period.  An overview of the 
study design is presented in Figure 1. 


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All subjects who have completed screening assessments and are deemed eligible for the 
study will have a baseline CSF.  During the Treatment Period study visits were conducted 
after 3, 6, 9, and 12 weeks on E2027.  Efficacy assessments were performed after 6 and 12 
weeks on E2027.  After subjects completed 9 weeks of treatment with E2027, a 2nd CSF 
sample was collected.  
Subjects who prematurely discontinued study drug for any reason underwent 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 were conducted at the 
ED Visit.  In addition, subjects who discontinued study drug were expected to continue in the 
study for the originally scheduled visits, starting with next such visit that was >7 days after 
the ED Visit.    
During the COVID-19 pandemic, and under other extenuating circumstances: 
• An extension of the Screening Period from 6 weeks to up to 10 weeks was allowed with 
sponsor approval on a subject by subject basis. 
• If subjects could not visit the study site, all procedures which required physical contact 
with the subjects (eg, vital signs, ECGs, blood tests, physical examination, Unified 
Parkinson’s Disease Rating Scale Part III: Motor Examination [UPDRS-III]) could be 
conducted via home visit (if feasible) with sponsor approval.  The brain or cardiac 
imaging during the Screening Visit was to be conducted at the study site.  The CSF 
collection at the Screening Visit and Visit 6 (Week 9) was to be conducted at the study 


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site.  Other study procedures including all the efficacy endpoints, adverse events (AEs), 
and concomitant medications review could be conducted remotely via telephone, sponsor 
approved telehealth, or home visit.  If it was not possible for subjects to attend the study 
site for the CSF collection Visit 6 (Week 9), this could be performed at an Unscheduled 
Visit as soon as possible after Week 9.  Study drug was to be delivered to subjects’ 
homes if it was not possible to visit the study site to collect the study drug.   
4 
DETERMINATION OF SAMPLE SIZE 
Assuming the standard deviation of percentage change from baseline in CSF cGMP at 
Week 9 was 60, the sample size of 6 completers per subgroup (for 8 enrolled subjects per 
subgroup, assuming a 25% dropout rate), would have approximately 80% power to detect the 
difference in change from baseline of CSF cGMP of 100% between the DLB without 
amyloid copathology subgroup and the DLB with amyloid copathology subgroup.  The 
analysis between the PDD without amyloid copathology subgroup and the PDD with amyloid 
copathology subgroup, also would have approximately 80% power to detect the difference in 
change from baseline of CSF cGMP of 100% (same assumptions as above).  These sample 
size calculations illustrated the possible differences that could be seen between subgroups.  
However, without previous data on the differences between subgroups in CSF cGMP, these 
were for illustration only and it was not expected statistical significance would be reached 
with 6 subjects per subgroup. 
The probability of observing a difference in percentage of CSF cGMP between 2 subgroups 
(DLB without amyloid copathology subgroup minus DLB with amyloid copathology 
subgroup, or PDD without amyloid copathology subgroup minus PDD with amyloid 
copathology subgroup) ≥30% depends on the true difference between the 2 subgroups.  If the 
true difference was 100%, there would be 97.8% probability that the observed difference was 
≥30%.  If the true difference was 60%, the probability was 80.7%.  If the true difference was 
10%, there would be 28.2% probability that the observed difference was ≥30%. 
5 
STATISTICAL METHODS 
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 
5.1.1 
Primary Endpoint 
Percentage change from baseline in CSF cGMP at 9 weeks of treatment.  
5.1.2 
Secondary Endpoints 
• Safety and tolerability of E2027 as measured by the following: 
- 
Incidence of adverse events including severe AEs, serious AEs, AEs resulting in 
discontinuation   


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- 
Incidence of orthostatic hypotension and orthostatic tachycardia   
- 
Incidence of markedly abnormal laboratory values and shifts from baseline of 
laboratory values   
- 
Incidence of abnormal ECG parameters and abnormal ECG findings   
- 
Incidence of suicidality based on Columbia Suicide Severity Rating Scale (C-SSRS)   
- 
Changes from baseline in the total score of MDS-UPDRS-III  
 
5.1.3 
Exploratory Endpoints  
• The following clinical efficacy endpoints at 12 weeks of treatment 
- 
Change from baseline in MoCA total score 
- 
Change from baseline in WAIS-IV DSC score 
- 
CIBIC-Plus scale 
- 
CGIC scale 
- 
Change from baseline in CFI score 
- 
Change from baseline in MMSE total score 
- 
Change from baseline in NPI total score, subscores and caregiver distress score 
- 
Change from baseline in SAPS-PD total score 
- 
Change from baseline in FAQ total score 
• Change from baseline in CSF cGMP at 9 weeks of treatment 
• Percentage change and change from baseline at 9 weeks of treatment in other biomarkers 
in CSF and/or plasma, including using other diagnostic subgroups classifications based 
on baseline biomarkers (if appropriate) 
• PK of E2027 in subjects with DLB or PDD, using population modelling 
• Relationships between E2027 in plasma/CSF and its effects on the following variables  
using PK/PD modelling, if data permit: 
- 
Plasma/CSF PD biomarkers (including CSF cGMP),  
- 
Clinical efficacy (including MoCA, WAIS-IV DSC, CIBIC-Plus, NPI, MMSE, CFI, 
SAPS-PD, FAQ, and CGIC at 12 weeks of treatment),  
- 
Safety variables 
• Relationships of the plasma and CSF PD biomarkers compared to MoCA, WAIS-IV 
DSC, CIBIC-Plus, NPI, MMSE, CFI, SAPS-PD, FAQ, and CGIC at 12 weeks of 
treatment, if data permit 
• Relationships amongst plasma biomarkers and CSF biomarkers at baseline and after 
treatment (if appropriate)  
• Subgroup analyses based on genotype classification for CSF cGMP changes from 
baseline and clinical endpoints 


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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 post baseline safety assessment.   
The Full Analysis Set (FAS) is the group of subjects who receive at least 1 dose of study 
drug and have baseline and at least 1 post baseline MoCA measurement. 
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 
1 PD parameter. Subjects who have low drug compliance based on their PK results will be 
excluded from the PD Analysis Set. Lack of drug around the Week 9 CSF will affect the 
results of the CSF cGMP, and hence distort the primary endpoint interpretation.  
 
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 electronic case report form (eCRF).  The distribution of the number of subjects 
enrolled by each site will be summarized by subgroup and overall.   
Study Completion, defined as completing 12 weeks of study and the follow up visit:  The 
number (percent) of 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 subgroup and total for all subjects.  
Completion of Study Treatment, defined as completing 12 weeks of study:  The number 
(percent) of 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 
subgroup and total for all subjects.  Subjects who discontinued study treatment but were 
followed up for efficacy assessments after treatment discontinuation will also be 
summarized. 
5.2.3 
Protocol Deviations 
A summary table and listing will be produced with critical protocol deviations.  


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5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each subgroup and overall using descriptive statistics.  Continuous 
demographic and baseline variables include age, age at diagnosis, age at onset, years since 
onset of symptoms, NPI hallucintaions FxS score, body weight, height, disease duration, 
baseline MDS-UPDRS part III score, SFQ Score, Modified Hachinski Ischemic Scale, 
average time per day for caregiver to spend with patient, and average days per week for 
caregiver to spend with patient.  Categorical variables include sex, age group (less than 65 
years, age greater than or equal to 65 years), age group at diagnosis, age group at onset, race, 
ethnicity, treatment with AChEIs (no or yes), Columbia Classification Algorithm for Suicide 
Assessment (C-CASA), C-SSRS not completed (missing), Hoehn & Yahr stage and 
subgroups (0, I, II vs III, IV, V), NPI hallucintaions FxS score subgroups (<median, 
≥median), relationship of caregiver to patient, caregiver reside with the patient (yes or no), 
caregiver’s time per week to spend with subject (<median, ≥median), have each clinical DLB 
core feature (hallucination, fluctuation, parkinsonism, rapid eye movement sleep behavior 
disorder [RBD]) (yes or no), and have 2 or more core clinical DLB 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 of DLB, have each indicative 
biomarker of DLB, Parkinsonian Symptoms (yes or no), bradykinesia under PDD (Yes, No), 
at least one of the other clinical features of PDD (muscular rigidity, 4-6 Hz rest tremor, 
postural instability) (yes or no) , PDD symptoms severe enough to impair work/activities (yes 
or no).   
Biomarker data will be summarized under the PD Analysis Set for each subgroup and overall 
using descriptive statistics.  Continuous variables include CSF cGMP, plasma Aβ42, plasma 
Aβ40, CSF Aβ42, CSF Aβ40, CSF Aβ42/40 ratio, plasma p-tau181, plasma p-tau181/Aβ(1-
42), CSF p-tau181, CSF p-tau181/Aβ(1-42), plasma neurogranin, plasma neurofilament light 
(NfL), plasma GFAP, CSF neurogranin, CSF neurofilament light, and any other appropriate 
biomarkers.  Categorical variables include Aβ42/40 ratio (<0.092, ≥0.092), CSF Aβ42/40 
ratio (<0.0571, ≥0.0571) [Ref 1], ApoE4 (positive, negative), ApoE categories, plasma p-
tau181 (<2.2, ≥2.2 µg/mL), plasma p-tau181/Aβ(1-42) ratio (<0.043, ≥0.043), CSF total tau 
(<400, ≥400 µg/mL), CSF ptau-181 (<52.8, ≥52.8 µg/mL), CSF p-tau181/Aβ(1-42) ratio 
(<0.083, ≥0.083), CSF total tau/Aβ(1-42) ratio (<0.637, ≥0.637) and other groups of 
biomarkers as appropriate.  If numbers allow, combinations as follows will be calculated:  
a) Based on plasma Aβ42/40 and apolipoprotein E4 (ApoE4): 
• Aβ42/40 <0.092 and ApoE4 postive,  
• Aβ42/40 <0.092 and ApoE4 negative,  
• Aβ42/40 ≥0.092 and ApoE4 negative,  
• Aβ42/40 ≥0.092 and ApoE4 positive,  
b) Based on CSF Aβ42/40 and ApoE4 
• CSF Aβ42/40 <0.0571 and ApoE4 postive,  


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• CSF Aβ42/40 <0.0571 and ApoE4 negative,  
• CSF Aβ42/40 ≥0.0571 and ApoE4 negative,  
• CSF Aβ42/40 ≥0.0571 and ApoE4 positive. 
 
Clinical efficacy data will be summarized under the FAS for each subgroup and overall using 
descriptive statistics.  Continuous variables include MoCA total score, NPI total score, NPI-4 
score, NPI-10 score, NPI-D score, NPI subscores, MMSE total score, CFI score, WAIS-IV 
DSC, SAPS-PD and FAQ.  Catergorical variables include CIBIC Plus and subitems, and 
MMSE total score subgroup (14-19, 20-26). 
Where Screening values are 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 23.1 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.  
The number (percent) of subjects will be presented by SOC and PT for each subgroup and 
total.  
5.2.5 
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 2020).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by subgroup and overall, Anatomical Therapeutic Chemical (ATC) 
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. 
Prior and concomitant medications will be summarized by cognitive and non-cognitive 
medications categorized under DLB and PDD medications, all other medications not 
categorized under DLB and PDD medications will be summarized separately. 
Restricted medications taken at baseline, and changes in restricted medications taken at any 
time post baseline will be summarized separately.  Prohibited medications will be 
summarized separately if numbers allow. 


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Medications taken within the 4-week Follow-Up Period will also be listed. 
5.2.6 
Treatment Compliance 
Percent compliance will be calculated for the Safety Analysis Set as follows: 
Compliance = (Total number of capsules dispensed – Total number of capsules returned – 
Total Number of capsules lost) x 100% / Planned Total number of capsules 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 subgroup.   Subjects will also be categorized by compliance criteria 
<50%, ≥50% to <80%, ≥80% to ≤100%, >100% to ≤120%, >120% and missing. The 
maximum of planned total number of capsules to be taken will be 168 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
This is a multi-center study conducted in United States and Canada.  Due to the small 
number of subjects per site and location of sites, subjects from all centers will be pooled for 
all summaries and analyses. 
5.3.2 
Adjustments for Covariates 
Where statistical analysis models are used, the baseline of the variable will be included as a 
covariate. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
5.3.4 
Examination of Subgroups 
The primary subject subgroups will be compared for all data: 
• DLB without amyloid copathology versus DLB with amyloid copathology, and PDD 
without amyloid copathology versus PDD with amyloid copathology).  Amyloid 
copathology is defined by the plasma Aβ42/40 ratio: with <0.092, without ≥0.092.  
• The above subgroups will be combined to compare with amyloid vs without amyloid 
copathology, DLB without amyloid vs PDD without amyloid, and DLB with amyloid 
vs PDD with amyloid). 
The demography, MoCA and some of the PD endpoints will be presented by the subgrouping 
as column headers instead of the amyloid copathology: 
• Plasma p-tau181/Aβ(1-42) (<0.043, ≥0.043), by DLB, PDD and Overall 


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• CSF amyloid status (CSF Aβ42/40 <0.0571, CSF Aβ42/40 ≥0.0571), by DLB, PDD 
and Overall  
• Genotype classification (ApoE4 postive or negative), by DLB, PDD and Overall 
• Plasma p-tau181 (<2.2, ≥2.2), by DLB, PDD and Overall 
• CSF p-tau181 (<52.8, ≥52.8), by DLB, PDD and Overall 
• CSF p-tau181/ Aβ42 (<0.083, ≥0.083), by DLB, PDD and Overall 
• CSF total tau/Aβ42 (<0.637, ≥0.637), by DLB, PDD and Overall 
• If data permits, combinations of the above overall for DLB+PDD,  
- 
a) plasma Aβ42/40 <0.092 and ApoE4 postive, Aβ42/40 <0.092 and ApoE4 
negative, Aβ42/40 ≥0.092 and ApoE4 negative, Aβ42/40 ≥0.092 and ApoE4 
positive. 
b) CSF Aβ42/40 <0.0571 and ApoE4 postive, CSF Aβ42/40 <0.0571 and ApoE4 
negative, CSF Aβ42/40 ≥0.0571 and ApoE4 negative, CSF Aβ42/40 ≥0.0571 and 
ApoE4 positive. 
• Other biomarkers, to be determined if data permit (all cutpoints TBD). 
Additional subgroup analyses may also be conducted, if deemed appropriate. 
Where subgroups are small, summaries and analyses will be produced, caution will be used 
in the interpretation of those subgroups. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
5.3.5.1 
Efficacy  
For the efficacy endpoints, there will be no imputation of missing value.  
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 Study 
Data Tabulation Model (SDTM) Domain Mapping Specifications Template and documented 
in SDTM+ specification.  
All the listings will display the original missing values. 
5.3.6 
Other Considerations 
Not Applicable. 


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5.4 
Efficacy Analyses 
5.4.1 
Primary Efficacy Analyses 
Not applicable. 
5.4.2 
Secondary Efficacy Analyses 
Not applicable. 
5.4.3 
Other Efficacy Analyses 
Exploratory efficacy analyses are described in Section 5.8 Exploratory Analyses. 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
E2027 plasma and CSF concentrations were obtained during the dosing period (Week 9 for 
plasma for biomarkers, Weeks 6, 9 and 12 for plasma for PK and Screening and Week 9 for 
CSF).  Details of the analysis methods for population PK/PD modeling will not be described 
in this SAP but will be described in a separate analysis plan. 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for E2027 concentration listings and for summaries of 
E2027 concentrations in plasma and CSF by dose and day.   
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 and 
2 studies.  As appropriate, the effect of covariates on the PK of E2027, such as baseline 
characteristics/demographics will be evaluated.  Derived exposure parameters such as steady 
state area under the concentration time curve or average concentration of E2027 and other 
derived parameters may be calculated from the final PK model using the individual posterior 
estimates of the PK parameters and dosing history.  The details will be described in the 
separately prepared analysis plan. 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacodynamic Analyses 
The PD Analysis Set will be used for the summaries and analyses of CSF and plasma PD 
biomarkers.  The percentage change from baseline in CSF cGMP at 9 weeks of treatment will 
be analyzed to compare different subject subgroups (DLB without amyloid copathology vs 
DLB with amyloid copathology, and PDD without amyloid copathology vs PDD with 
amyloid copathology). Secondary comparisons will be: total (DLB+PDD) without amyloid 
vs with amyloid,  DLB without amyloid vs PDD without amyloid, and DLB with amyloid vs 
PDD with amyloid.  


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Analyses, comparing the different subgroups, of the percentage change from baseline in CSF 
cGMP will be performed using an analysis of covariance, where baseline CSF cGMP will be 
included as a covariate.  The least square (LS) means, LS mean subgroup differences and 
95% CIs will be presented. 
The change from baseline in CSF cGMP at 9 weeks of treatment will also be analyzed.  
Other CSF and plasma PD biomarkers (CSF amyloid, plasma p-tau181, CSF p-tau181, 
plasma neurogranin, plasma neurofilament, CSF neurogranin, CSF neurofilament, etc) may 
be analyzed similarly, if appropriate. 
The CSF and plasma PD biomarkers (both percentage change and change from baseline at 9 
weeks) will be summarized by subgroups, as defined in section 5.3.4.   
Summaries and figures will be produced exploring the relationships between CSF and plasma 
PD biomarkers and the efficacy endpoints. If data permit, the relationship between CSF and 
plasma PD biomarkers compared to each efficacy endpoint (MoCA, WAIS-IV DSC, CIBIC-
Plus, CGIC, CFI, MMSE, NPI [NPI-12, NPI-10, NPI-4 and NPI-D, and each subscore], 
SAPS-PD and FAQ) and MDS-UPDRS-III will be explored using correlation analysis. The 
association between individual CSF/plasma biomarker concentration data and individual 
efficacy data within each subgroup (DLB without amyloid copathology vs DLB with 
amyloid copathology; PDD without amyloid copathology vs PDD with amyloid copathology; 
total (DLB+PDD) without amyloid vs with amyloid; DLB without amyloid vs PDD without 
amyloid; and DLB with amyloid vs PDD with amyloid) will be examined through scatter 
plots.  The scatter plots including the Pearson correlation coefficient and Spearman 
correlation coefficient will be produced for each amyloid subgroup for both percentage 
change from baseline and change from baseline (as appropriate) in CSF and plasma PD 
biomarkers after 9 weeks of treatment and change from baseline at 12 weeks of treatment for 
the efficacy endpoints. Correlations against CSF and plasma biomarkers at baseline 
compared to change from baseline at 12 weeks of treatment for the efficacy endpoints may 
also be explored, by subgroups.   
If appropriate, relationships amongst plasma biomarkers and CSF biomarkers (including 
cGMP) at baseline and after treatment will be explored using summaries, correlation analysis 
and scatter plots. 
Pharmacogenomic Analyses 
The percentage change in CSF cGMP at 9 weeks, change in CSF cGMP at 9 weeks and other 
CSF and plasma PD biomarkers will be summarized by ApoE4 status, using the PD Analysis 
Set.  Other pharmacogenomic data will be summarized similarly.   
Pharmacodynamic/Pharmacokinetic Analyses 
The correlation amongst plasma and CSF exposure to E2027 and the various efficacy and 
biomarker endpoints will be explored graphically.  The details will be described in the 
separately prepared analysis plan. 


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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), MDS-UPDRS-III, along with change from 
baseline in laboratory safety test variables, ECGs, and vital sign measurements (including 
orthostatic changes) will be summarized by subgroup and overall. 
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 subgroup and overall.  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 subgroup and overall.  Overall exposure (number of 
subject-weeks) is defined as summation over all subjects’ exposure durations and will be 
summarized by subgroup and overall. 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the MedDRA.  Adverse events will be coded to the 
MedDRA (Version 21.0 or higher) LLT closest to the verbatim term.  The linked MedDRA 
PT and primary SOC will also be captured in the database. 
A 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 subgroup and overall, 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 


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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. 
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 subgroup and overall.  A subject data 
listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each subgroup and overall.  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 AEs 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 9.5.1.4.4. 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, subgroup and overall, using descriptive statistics.  Qualitative 
parameters listed in protocol Section  9.5.1.4.4 will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline to each postbaseline 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 subgroup 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 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 


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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. 
5.6.4 
 Vital Signs 
Descriptive statistics for vital signs parameters (diastolic blood pressure [DBP] and systolic 
blood pressure [SBP], heart rate [HR], 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 subgroup and overall. 
Orthostatic hypotension is defined based on the following criteria per protocol: 
Drop in standing SBP ≥20 mmHg compared to supine, or drop in standing DBP ≥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 (ie, 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 subgroup 
and overall and visit. 
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 subgroup and overall.  Table 2 presents the clinical notable ranges. 


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Table 2 
Clinical Notable Ranges for Vital Signs 
Vital Sign 
Criterion for Low 
Criterion for High 
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 each postbaseline visit.  The mean QTc 
Fridericia (QTcF) and other ECG intervals based on triplicate ECG will be obtained.  
Descriptive statistics for ECG parameters (QTc Bazett, QTcF, PR interval QRS duration and 
RR interval) and changes from baseline will be presented by visit, subgroup and overall.  
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 postbaseline abnormal ECG 
result in QTc Fridericia during the treatment period will be summarized according to the 
following categories. 
Clinically borderline or abnormal ECG results QTcF 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 subgroup and overall, with at least 1 postbaseline 
abnormal ECG results during the treatment period, Weeks 3, 6, 9 and 12 (and ED, as needed) 
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.  
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 the Treatment 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 the Treatment 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 
MDS-UPDRS-III 
Changes from baseline in the total score and four subscores of MDS-UPDRS-III will be 
summarized using descriptive statistics for continuous variable by visit and treatment group.  
No formal statistical analyses will be performed. Figures will be produced by visit, they will 
present without amyloid DLB, with amyloid DLB, without amyloid PDD, with amyloid 
PDD, with amyloid and without amyloid copathology (regardless of DLB/PDD). 
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).  


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The 4 subscores are for tremor, rigidity, bradykinesia and postural instability and gait 
difficulty (PIGD), as calculated per Section 8.5. 
 
5.7 
Other Analyses 
Not applicable. 
5.8 
Exploratory Analyses 
The exploratory efficacy endpoints, MoCA (and subitems), WAIS-IV DSC, CIBIC-Plus (and 
subitems), CGIC, CFI, MMSE, NPI (NPI-12, NPI-10, NPI-4 and NPI-D, and each subscore), 
SAPS-PD and FAQ, will be summarized based on the FAS, by subject subgroup (DLB 
without amyloid copathology, DLB with amyloid copathology, PDD without amyloid 
copathology, and PDD with amyloid copathology).  No formal statistical analyses will be 
performed. Figures will be produced by visit, they will present without amyloid DLB, with 
amyloid DLB, without amyloid PDD, with amyloid PDD, with amyloid and without amyloid 
copathology (regardless of DLB/PDD). 
The exploratory efficacy endpoint, MoCA will be repeated for subgroups as per Section 
5.3.4. 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
No changes have been made. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Efficacy data handling  
 
8.1.1 
Pretreatment/Baseline Efficacy 
Baseline for all efficacy endpoints is defined as the last pretreatment assessment.  
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.   
 


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Table 3 
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) 
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.  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. 
 
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 ED Visit.  The scheduled visits 
post ED will be flagged in the listings and datasets to reflect its post ED status.     
8.2 
PD data handling  
8.2.1 
Pretreatment/Baseline PD 
Baseline for all PD endpoints is defined as the last pretreatment assessment.  
8.2.2 
Treatment Duration for PD 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.   
 


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Table 4 
Mapping of Study Day Ranges to Week for PD 
 
Windowing Period 
Study Day Range  
(Relative to First Dose) 
Week 
Screening 
(-42) ≤ Day ≤ (-8) 
 
Analysis Baseline 
- 
a 
Treatment 
1 ≤ Day ≤ 98 
9 
a:  All pretreatment assessments are conducted during Screening before Day 1. The Analysis Baseline is the last 
non-missing value measured during pretreatment phase. 
8.2.3 
Duplicate PD Tests 
The following rule will be performed if duplicate results are received on biomarker data, if 
back up samples are tested in addition to the primary samples: 
1) Deviation between first and second result ≤ 15 %. Accept first result. 
2) deviation between first and second result > 15% and ≤ 30%.  Report the mean of the first 
and second result. 
3) Deviation between first and second result > 30%.  Present as missing data. 
Deviation= 100%* (second result – first result)/first result 
8.3 
Safety data handling  
8.3.1 
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. 
8.3.2 
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 5 gives the mapping of relative 
day ranges to week for non-AE safety variables.  If a subject did not have a recorded 


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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 2 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 2 assessments are equidistant from the scheduled assessment then the last 
assessment of the 2 (within the allowable window) will be used. 
 
Table 5 
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) 
 
Analysis Baseline 
- 
a 
Treatment 
1 ≤ Day ≤ 32 
3 
Treatment 
33 ≤ Day ≤ 53 
6 
Treatment 
54 ≤ Day ≤ 74 
9 
Treatment 
75 ≤ Day ≤ 98 
12 (d) 
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.   
d: For assessments with no Week 3/6/9 planned assessments (ie UPDRS), 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. For Lab data (and other similar data) where only Week 6 and 12 are performed, 
the window for W eek 6 is 1 ≤ Day ≤ 53, and Week 12 the window is 54 ≤ Day ≤ 98. 
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.   
 


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8.3.3 
Handling of Replicate Data  
A subject having an AE coded to the same PT 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. 
8.3.4 
Safety Data Collected After the ED Visit   
Post TE data (data collected beyond treatment emergent window) will be summarized 
separately for  for non-TEAEs only, otherwise no post TE data will be summarized.  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.   
8.4 
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, WAIS-IV DSC, SAPS-PD and 
FAQ. 
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: 


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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.  
The NPI Total Score (range 0 to 144) = sum of all item scores.  If any item score is missing it 
is set to zero.  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 it is set to zero 
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 it is set to zero. 
Mini-Mental State Examination (MMSE)   
The MMSE is composed of 30 questions grouped into domains, see Table 6.  For each of the 
MMSE domains the correct responses are added.  If a domain has missing data then the 
domain is missing.  From the domains compute the six items as show in Table 6.  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. 


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Table 6 
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 
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 perform 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.  If any one of the domain scores 
are missing then the score is missing. 
Wechsler Adult Intelligence Scale-4th Edition Digit Symbol Coding (WAIS-IV DSC) 
The measure of interest in the WAIS-IV is known as the Digit Symbol Coding, which is the 
number of squares filled in correctly within the time limit of 120 seconds (score range of 0 
to135).  This test engages multiple cognitive abilities including attention, psychomotor speed, 


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complex scanning, visual tracking, and immediate memory.  If any part of the test is missing 
(subject unable or unwilling) then the score is missing.  
Scale for Assessment of Positive Symptoms in Parkinson’s Disease (SAPS-PD) 
There are 5 items for hallucinations (including auditory, voices conversing, somatic/tactile, 
visual and global hallucinations) and 4 items for delusions (including persecutory, jealousy, 
reference and global delusions).  Each item is scored on a scale of 0 to 5, with 0 being none 
and 5 representing severe and frequent symptoms.  Therefore, the SAPS-PD total score can 
range from 0 to 45 with higher scores reflecting greater severity of illness.  If any one of the 
item scores are missing, then the total score is missing. 
   
Funtional Assessments Questionnaire (FAQ) 
On the basis of interviews with the caregivers/informants, subjects will be rated for ability to 
carry out ten complex activities of daily living:  (1) manage finances, (2) complete forms, 
(3) shop, (4) perform games of skill or hobbies, (5) prepare hot beverages, (6) prepare 
balanced meal, (7) follow current events, (8) attend to television programs, books, and 
magazines, (9) remember appointments, and (10) travel out of the neighborhood.  Each 
activity will be rated as 0 (normal, does without difficulty), 1 (has difficulty but does by self), 
2 (requires assistance), or 3 (dependent).  Scores will be summed across items to provide a 
total disability score (higher scores = greater impairment; maximum score = 30).  If an 
activity was never or very rarely performed premorbidly, it will be marked as “Not 
Applicable” and will not be included in the score.  A proportional score will be derived for 
subjects who mark any activity as ‘Not Applicable’ as follows (achieved score/(30 – 3 times 
the number of activities marked ‘Not Applicable’).   
8.5 
Algorithms for Safety Parameters  
MDS-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). 
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]). 


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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). 
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 using SAS Version 9.4 or later.    
11 MOCK TABLES, LISTINGS, AND GRAPHS 
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. Table 4 in PERFORMANCE OF CSF AD BIOMARKERS IN PREDICTING AMYLOID 
PET POSITIVITY IN EARLY AD: DATA FROM EISAI’S MISSIONAD PROGRAM, 
Kaplow et al, Presented at the 15th International Conference on Alzheimer’s and Parkinson’s 
Diseases: Mechanisms, Clinical Strategies and promising Treatments of Neurodegenerative 
Diseases. (AD PD 2021), March 9-14, 2021, Virtual Event. Poster Board Number: P220. 


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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 3. 
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 – 2.5×ULN if 
baseline was normal; 
2.0 – 2.5×baseline if 
baseline was abnormal 
>2.5 – 5.0×ULN if 
baseline was normal; 
>2.5 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
ALT 
>ULN – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 5.0×ULN if 
baseline was normal; 
3.0 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
AST 
>ULN – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 5.0×ULN if 
baseline was normal; 
3.0 – 5.0×baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 – 20.0×baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0×baseline if 
baseline was 
abnormal 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN if 
baseline was normal; 
1.0 – 1.5×baseline if 
baseline was abnormal 
>1.5 – 3.0×ULN if 
baseline was normal; 
1.5 – 3.0×baseline if 
baseline was abnormal 
>3.0 – 10.0×ULN if 
baseline was normal; 
3.0 – 10.0×baseline if 
baseline was abnormal 
>10.0×ULN if 
baseline was normal; 
>10.0×baseline if 
baseline was 
abnormal 


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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium <LLN 
- 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium <1.0 - 
0.9 mmol/L; 
symptomatic 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium <0.9 - 
0.8 mmol/L; 
hospitalization indicated 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium 
<0.8 mmol/L; life-
threatening 
consequences 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium >ULN 
- 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium >1.5 - 
1.6 mmol/L; 
symptomatic 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium >1.6 - 
1.8 mmol/L; 
hospitalization indicated 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences 
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×baseline; 
>1.5 – 3.0×ULN 
>3.0×baseline; 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 2.5×ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal 
>2.5 – 5.0×ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal 
>5.0 – 20.0×ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal 
>20.0×ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Glucose, serum-high (hyperglycemia) 
Abnormal glucose 
above baseline with no 
medical intervention 
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes 
Insulin therapy initiated; 
hospitalization indicated 
 
life-threatening 
consequences; urgent 
intervention indicated 
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)  
Laboratory finding 
only and intervention 
not indicated 
Oral replacement 
therapy indicated 
 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated 
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; 
intervention initiated 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 


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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
125-129 mmol/L and 
asymptomatic 
<125 – 129 mmol/L 
symptomatic; 
120 - 124 mmol/L 
regardless of symptoms 
<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 without 
physiologic 
consequences  
N/A 
>ULN with physiologic 
consequences  
  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = gamma-glutamyl transferase, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.   
 
 


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SIGNATURE PAGE 
Author:   
 
 
 
 
 
 
 
 
 Neurology Business Group 
 
Date 
Approval: 
 
 
 
 
 
 
 
 
 Neurology Business Group 
 
Date 
 
 
 
 
 
 of Neurology Business Group 
 
  
Neurology Business Group 
 
Date 
 
 
 
 
 
Study Director 
 
 
Neurology Business Group 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD