Clinical trial NCT04971733
Conditions: Alzheimer Disease
Keywords: E2814 Alzheimer disease Dominantly inherited Alzheimer disease Mild and moderate cognitive impairment Central nervous system disease
Sponsor: Eisai Inc.
Start date: 2021-06-28; Completion date: 2024-05-24
Enrollment: 8 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of the study is to assess the safety and tolerability of intravenous (IV) infusions of E2814 in participants with dominantly inherited Alzheimer's disease (DIAD), and to evaluate target engagement (TE) of E2814 on microtubule binding region (MTBR)-tau species in cerebrospinal fluid (CSF) in participants with DIAD.

Detailed description:

Arms: arm 1: Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b and over 96 weeks in Phase 2. arm 2: Participants will receive E2814 as an intravenous infusion at set intervals over 52 weeks.
Interventions: intervention 1: E2814
Intervention descriptions: intervention 1: E2814 intravenous infusion.

Protocol documents:
Prot_000.pdf: 


Clinical Study Protocol
Incorporating Amendment 04
E2814-G000-103
Eisai
FINAL (V6.0): 01 Dec 2023
Confidential
Page 2 of 89
Revisions to Version 5.0 (per Amendment 04)
Date:  01 Dec 2023
Change
Rationale
Affected Protocol Sections
Updated Cohort B Schedule 
of Procedures/Assessments 
footnote k
To clarify blood sampling time 
points for PK assessments
Section 9.5.2.1
Revisions to Version 4.0 (per Amendment 03)
Date:  28 Feb 2023
Change
Rationale
Affected Protocol Sections
Added new Cohort (B) and 
increased the number of 
subjects
To further evaluate safety and 
biomarker effects at the 3000 mg 
dose.
Synopsis

Study Design

Number of Subjects

Study Treatments

Duration of Treatment

Clinical Efficacy Assessments

Pharmacokinetic Assessments

Pharmacodynamic, 
Pharmacogenetic, and Other 
Biomarker Assessments

Safety Assessments

Immunogenicity Assessments

Sample Size Rationale
Section 9.1
Section 9.1.1.1
Section 9.1.2.2
Section 9.2
Section 9.3
Section 9.4.1
Section 9.5.1.1
Section 9.5.1.1.4
Section 9.5.1.2
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.1.4
Section 9.5.1.4.4
Section 9.5.1.4.5
Section 9.5.1.4.6
Section 9.5.1.4.7
Section 9.5.1.4.8


Clinical Study Protocol
Incorporating Amendment 04
E2814-G000-103
Eisai
FINAL (V6.0): 01 Dec 2023
Confidential
Page 3 of 89
Revisions to Version 4.0 (per Amendment 03)
Date:  28 Feb 2023
Change
Rationale
Affected Protocol Sections
Section 9.5.1.5
Section 9.5.2.1
Section 9.5.2.2
Clarified primary endpoint of 
change from baseline in CSF 
free and bound MTBR-tau and 
total MTBR-tau at 12 weeks is 
for Cohort A only
Clarification due to addition of 
Cohort
Synopsis

Statistical Methods
Section 9.7.1.1.1
Added pharmacokinetic and 
anti-drug antibody blood 
sampling as required 
assessments at the Follow-up 
Visit
Correction
Synopsis

Pharmacokinetic Assessments

Immunogenicity Assessments
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.2.1
Revisions to Version 3.0 (per Amendment 02)
Date:  18 Oct 2022
Change
Rationale
Affected Protocol Sections
Added 4500 mg dose
Results to date from study 
E2814-A001-001 indicate that a dose 
of 4500 mg is acceptable for 
evaluation in subjects with 
Alzheimer’s disease in order to 
inform clinical dose selection for 
Phase 3 studies
Synopsis

Study Design

Study Treatment
Section 9.1
Section 9.1.2
Section 9.2
Section 9.4.1
Section 9.4.4
Section 9.4.5
Section 9.5.1.3.1  
Section 9.5.1.3.2
Section 9.5.2.1
Added cerebrospinal fluid 
(CSF), biomarker, 
pharmacokinetic (PK), and 
immunogenicity sampling 
associated with the 
1st 4500 mg dose
To collect data at the appropriate 
times related to the increased dose
Synopsis

Study Design

Pharmacokinetic Assessments

Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Assessments

Immunogenicity Assessments
Section 9.5.1.3.1  


Clinical Study Protocol
Incorporating Amendment 04
E2814-G000-103
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FINAL (V6.0): 01 Dec 2023
Confidential
Page 4 of 89
Revisions to Version 3.0 (per Amendment 02)
Date:  18 Oct 2022
Change
Rationale
Affected Protocol Sections
Section 9.5.1.3.2
Section 9.5.1.5
Section 9.5.2.1
Clarified that subjects must be 
on a stable dose of oral 
contraception for 100 days 
prior to dosing and continue
on that dose throughout the 
study and for 16 weeks after 
study drug discontinuation
To correct error and ensure 
consistency in subject surveillance
for 5 half-lives after study drug
discontinuation
Synopsis

Exclusion Criteria
Section 9.3.2
Allow the use of marijuana 
(including products containing 
tetrahydrocannabinol [THC]) 
as a concomitant medication if 
the investigator confirms that 
there is no suspected abuse or 
dependency related to 
marijuana and THC use will 
not prevent the subject from 
performing psychometric tests 
accurately
To allow for subject use during the 
study
Synopsis

Concomitant Drug Therapy
Section 9.4.7
Allow Assessments for study 
visits that require positron 
emission tomography (PET), 
magnetic resonance imaging 
(MRI), and/or cognitive 
assessments to be completed 
over several days if needed 
provided all assessments are 
completed within the visit 
window
Clarification
Section 9.5.2.1
Updated sponsor address
Physical address change
Section 1
Updated signature page
Sponsor personnel changes
Protocol Signature Page
Revisions to Version 2.0 (per Amendment 01)
Date:  23 Nov 2021
Change
Rationale
Affected Protocol Sections
Edited the description of the timing of 
magnetic resonance imaging (MRI)
Revised for clarity
Synopsis
Safety Assessments
Section 9.5.1.4


Clinical Study Protocol
Incorporating Amendment 04
E2814-G000-103
Eisai
FINAL (V6.0): 01 Dec 2023
Confidential
Page 5 of 89
Revisions to Version 2.0 (per Amendment 01)
Date:  23 Nov 2021
Change
Rationale
Affected Protocol Sections
Added a row to the Schedule of 
Procedures/Assessments table to specify 
that Clinical Dementia Rating – Sum of 
Boxes (CDR-SB) is to be conducted at 
Screening
Added for clarity
Section 9.5.2.1
Revisions to Version 1.0 (per Amendment 01)
Date:  23 Nov 2021
The primary reason for the Amendment is to increase the dose of E2814 to be used in the 
Phase 2 part of this study. 
Change
Rationale
Affected Protocol Sections
Introduction of a higher dose 
(3000 mg) in the Phase 2 
Treatment Period
Following consultation with FDA and
given the totality of the nonclinical 
data and clinical safety and target 
engagement (TE) data available to 
date, a higher dose does not pose an 
unacceptable risk and provides for the 
evaluation of a higher E2814 dose in 
subjects with Alzheimer’s disease to 
inform clinical dose selection for 
Phase 3 studies.
Synopsis
Study Design
Study Treatments
Pharmacokinetic Assessments
Section 9.1.2.1.2
Section 9.2
Section 9.4.1
Section 9.4.4
Section 9.4.5
Section 9.5.1.3.1
Section 9.5.2.1
Revised the schedule of 
lumbar puncture for 
cerebrospinal fluid (CSF)
collection
Added a CSF collection to occur 
12 weeks after initiation of the highest
dose (3000 mg) to provide for the 
evaluation of target engagement and 
E2814 concentration at this dose.
Synopsis
Study Design
Pharmacokinetic Assessments
Pharmacodynamic 
Pharmacogenomic, and Other 
Biomarker Assessments
Section 9.1.2.1.2
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.2.1
Revised the schedule of 
cognitive assessments
Shifted the schedule of cognitive tests 
to occur every 24 weeks throughout 
the study, as changes in cognition are 
not likely to be observable over 
shorter intervals and to reduce the 
burden for study subjects and partners.
Synopsis
Clinical Efficacy Assessments
Section 9.5.1.2
Section 9.5.2.1
Deleted the requirement for a 
second informed consent 
The study is a continuous study from
the Phase 1b Treatment Period into the 
Phase 2 Treatment Period.  
Section 9.5.2.1


Clinical Study Protocol
Incorporating Amendment 04
E2814-G000-103
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FINAL (V6.0): 01 Dec 2023
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Page 6 of 89
Revisions to Version 1.0 (per Amendment 01)
Date:  23 Nov 2021
The primary reason for the Amendment is to increase the dose of E2814 to be used in the 
Phase 2 part of this study. 
Change
Rationale
Affected Protocol Sections
scheduled for the start of the 
Phase 2 Treatment Period
Explanation of the dose increases in 
Phase 2 is provided in the initial 
consent, and a separate consent to 
increase dose is not required.  
Added time window 
allowances for scheduled 
assessments
To provide flexibility to subjects and 
study partners.
Section 9.5.2.1
Increased blood volume 
collected for PD analyses 
from 6 mL to 10 mL
To provide sufficient plasma volume 
for all proposed PD biomarker 
analyses
Synopsis

Pharmacodynamic 
Pharmacogenomic, and Other 
Biomarker Assessments
Section 9.5.1.3.2
Corrected the PK sampling 
schedule to reflect that no PK 
sample is required on Day 84
Corrected for consistency throughout 
the protocol
Section 9.5.2.1
Section 9.5.1.3.1
Revised the time window 
allowance for vaccinations
relative to dosing, and added
instruction for the timing of 
COVID-19 vaccination
relative to dosing
To allow flexibility for subjects to 
undergo vaccination during ongoing 
COVID-19 pandemic
Synopsis
Concomitant Drug/Therapy
Section 9.4.7
Increased the duration of 
contraception requirement 
post-dosing and required post-
dose interval for reporting 
pregnancy or breast feeding
To maintain contraception and 
pregnancy reporting for 5 half-lives 
after the last dose
Synopsis
Exclusion Criteria
Section 9.3.2
Section 9.5.4.2
Increased the duration of the 
post-dose adverse event (AE) 
follow-up
To continue follow-up of AEs for 
5 half-lives after the last dose
Section 9.5.1.4.1
Deleted collection of 
subjects’ dates of birth
For consistency with Eisai Global 
Protocol template
Section 9.5.1.1.1
Revised the threshold of 
abnormal hepatic tests that 
may require reporting and 
additional evaluation for an 
underlying etiology
For consistency with Eisai Global 
Protocol template
Section 9.5.4.3.2
Revised the definition of the 
Safety Analysis Set for 
analysis
For consistency with Eisai Global 
Protocol template
Section 9.7.1.2
Editorial, internal consistency, 
and formatting revisions
Document quality
Throughout


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FINAL (V6.0): 01 Dec 2023
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Clinical Study Protocol
Incorporating Amendment 04
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FINAL (V6.0): 01 Dec 2023
Confidential
Page 8 of 89
1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E2814-G000-103
Study Protocol Title:
An Open-Label Phase 1b/2 Study to Assess Safety and Target 
Engagement of E2814 in Subjects with Mild to Moderate Cognitive 
Impairment due to Dominantly Inherited Alzheimer’s Disease 
Sponsor: 
Eisai Inc.
200 Metro Boulevard
Nutley, 
New Jersey 07110, US
Eisai Ltd. 
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire, AL10 9SN, UK
Sponsor’s Investigational 
Product Name:
E2814
Indication:
Alzheimer’s Disease
Phase:
1b/2
Approval Date:
V1.0
08 Dec 2020 
(original protocol)
V4.0
18 Oct 2022 
(Amendment 02)
V2.0
23 Nov 2021 
(Amendment 01)
V5.0
28 Feb 2023 
(Amendment 03)
V3.0
23 Nov 2021 
(Amendment 01)
V6.0
01 Dec 2023
(Amendment 04)
IND Number
139378
EudraCT Number
2020-005728-12
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.:  E2814
Name of Active Ingredient:  E2814
Study Protocol Title
An Open-Label Phase 1b/2 Study to Assess Safety and Target Engagement of E2814 in Subjects 
with Mild to Moderate Cognitive Impairment due to Dominantly Inherited Alzheimer’s Disease
Site(s)
Four or more sites across the United States (US) and United Kingdom (UK)
Study Period and Phase of Development
First subject screened to last subject’s last visit:  Approximately 41 months  (revised per 
Amendment 03)
Phase 1b/2
Objectives
Primary Objectives:

To assess the safety and tolerability of intravenous (IV) infusions of E2814 in subjects with 
Dominantly Inherited Alzheimer’s Disease (DIAD)

To evaluate target engagement (TE) of E2814 on microtubule binding region (MTBR)-tau 
species in cerebrospinal fluid (CSF) in subjects with DIAD
Secondary Objectives: 

To assess the pharmacokinetics (PK) of E2814 in serum, plasma, and CSF

To assess the immunogenicity (production of anti-E2814 antibody) of E2814

To assess the effect of E2814 on CSF, blood, and imaging biomarkers
Exploratory Objectives:
Study Design
This is an open-label Phase 1b/2 study to evaluate the safety and TE of E2814 on MTBR-tau 
species in CSF following IV infusions of E2814 in DIAD subjects.  Subjects in this study are 
confirmed mutation positive for genes known to be associated with DIAD.  The mutations in 
presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) that are 
associated with DIAD have very high penetrance (near 100%).  
The study will consist of 2 Cohorts (A and B). 
Cohort A
Cohort A consists of 2 phases:  A Screening Phase and a Treatment Phase consisting of 3 periods:
1b, 2, and follow up.
CCI
























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3
TABLE OF CONTENTS
REVISION HISTORY..........................................................................................................1
1
TITLE PAGE ................................................................................................................8
2
CLINICAL PROTOCOL SYNOPSIS............................................................................9
3
TABLE OF CONTENTS.............................................................................................21
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................26
5
ETHICS.......................................................................................................................29
5.1
Institutional Review Boards/Independent Ethics Committees.............................29
5.2
Ethical Conduct of the Study..............................................................................29
5.3
Subject Information and Informed Consent ........................................................30
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................31
7
INTRODUCTION.......................................................................................................31
7.1
Pathology of Alzheimer’s Disease......................................................................31
7.2
Compound Overview .........................................................................................32
7.3
Study Rationale..................................................................................................33
8
STUDY OBJECTIVES................................................................................................33
8.1
Primary Objectives.............................................................................................33
8.2
Secondary Objectives.........................................................................................33
8.3
Exploratory Objectives.......................................................................................34
9
INVESTIGATIONAL PLAN ......................................................................................34
9.1
Overall Study Design and Plan...........................................................................34
9.1.1
Pretreatment Phase ...................................................................................35
9.1.1.1
Screening Period...............................................................................35
9.1.2
Treatment Phase.......................................................................................36
9.1.2.1
Cohort A...........................................................................................36
9.1.2.1.1
Phase 1b Treatment Period..........................................................36
9.1.2.1.2
Phase 2 Treatment Period............................................................37
9.1.2.2
Cohort B  (revised per Amendment 03).............................................37
9.1.2.3
Follow-Up Period .............................................................................38
9.2
Discussion of Study Design, Including Choice of Control Groups......................38
9.3
Selection of Study Population ............................................................................38
9.3.1
Inclusion Criteria......................................................................................39
9.3.2
Exclusion Criteria.....................................................................................39
9.3.3
Removal of Subjects From Therapy or Assessment ..................................42
9.4
Treatments.........................................................................................................42
9.4.1
Treatments Administered..........................................................................42
9.4.2
Identity of Investigational Product............................................................42


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9.4.2.1
Chemical Name of E2814.................................................................42
9.4.2.2
Comparator Drug..............................................................................42
9.4.2.3
Labeling for Study Drug ...................................................................43
9.4.2.4
Storage Conditions ...........................................................................43
9.4.3
Method of Assigning Subjects to Treatment Groups.................................43
9.4.4
Selection of Doses in the Study ................................................................43
9.4.5
Selection and Timing of Dose for Each Subject........................................45
9.4.6
Blinding ...................................................................................................45
9.4.7
Prior and Concomitant Therapy................................................................45
9.4.8
Treatment Compliance .............................................................................46
9.4.9
Drug Supplies and Accountability ............................................................46
9.5
Study Assessments.............................................................................................48
9.5.1
Assessments .............................................................................................48
9.5.1.1
Screening Assessments.....................................................................48
9.5.1.1.1
Demography ...............................................................................48
9.5.1.1.2
Medical History ..........................................................................48
9.5.1.1.3
Viral Tests ..................................................................................48
9.5.1.1.4
Drug, Cotinine, and Alcohol Tests ..............................................48
9.5.1.2
Clinical Efficacy Assessments ..........................................................49
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................49
9.5.1.3.1
Pharmacokinetic Assessments.....................................................49
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments................................................................................50
9.5.1.4
Safety Assessments...........................................................................52
9.5.1.4.1
Adverse Events...........................................................................52
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................54
9.5.1.4.3
Study-Specific Adverse Events ...................................................55
9.5.1.4.4
Laboratory Measurements...........................................................56
9.5.1.4.5
Vital Signs and Weight Measurements........................................57
9.5.1.4.6
Physical Examinations ................................................................57
9.5.1.4.7
Electrocardiograms .....................................................................57
9.5.1.4.8
Other Safety Assessments ...........................................................58
9.5.1.5
Immunogenicity Assessments...........................................................58
9.5.2
Schedule of Procedures/Assessments........................................................58
9.5.2.1
Schedule of Procedures/Assessments................................................58


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9.5.2.2
Description of Procedures/Assessments Schedule .............................67
9.5.3
Appropriateness of Measurements............................................................67
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................67
9.5.4.1
Reporting of Serious Adverse Events................................................67
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................68
9.5.4.3
Reporting of Events Associated with Special Situations....................68
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................68
9.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........69
9.5.4.4
Expedited Reporting .........................................................................70
9.5.4.5
Breaking the Blind............................................................................70
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................70
9.5.5
Completion/Discontinuation of Subjects...................................................70
9.5.6
Abuse or Diversion of Study Drug............................................................70
9.5.7
Confirmation of Medical Care by Another Physician................................71
9.6
Data Quality Assurance......................................................................................71
9.6.1
Data Collection.........................................................................................71
9.6.2
Clinical Data Management .......................................................................71
9.7
Statistical Methods.............................................................................................71
9.7.1
Statistical and Analytical Plans.................................................................72
9.7.1.1
Study Endpoints................................................................................72
9.7.1.1.1
Primary Endpoints ......................................................................72
9.7.1.1.2
Secondary Endpoints...................................................................72
9.7.1.1.3
Exploratory Endpoints ................................................................72
9.7.1.2
Definitions of Analysis Sets..............................................................72
9.7.1.3
Subject Disposition...........................................................................73
9.7.1.4
Demographic and Other Baseline Characteristics..............................73
9.7.1.5
Prior and Concomitant Therapy ........................................................73
9.7.1.6
Efficacy Analyses.............................................................................73
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................73
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................73
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .....................................................................................74
9.7.1.7.3
Pharmacokinetic and Pharmacodynamic Analyses ......................74
9.7.1.8
Safety Analyses ................................................................................74


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9.7.1.8.1
Extent of Exposure......................................................................74
9.7.1.8.2
Adverse Events...........................................................................75
9.7.1.8.3
Laboratory Values.......................................................................76
9.7.1.8.4
Vital Signs ..................................................................................76
9.7.1.8.5
Electrocardiograms .....................................................................76
9.7.1.8.6
Other Safety Analyses.................................................................76
9.7.1.9
Other Analyses .................................................................................77
9.7.2
Determination of Sample Size ..................................................................77
9.7.3
Interim Analysis.......................................................................................77
9.7.4
Other Statistical/Analytical Issues ............................................................77
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................77
10
REFERENCE LIST.....................................................................................................77
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......79
11.1
Changes to the Protocol......................................................................................79
11.2
Adherence to the Protocol..................................................................................79
11.3
Monitoring Procedures.......................................................................................79
11.4
Recording of Data..............................................................................................80
11.5
Identification of Source Data..............................................................................80
11.6
Retention of Records..........................................................................................81
11.7
Auditing Procedures and Inspection ...................................................................81
11.8
Handling of Study Drug .....................................................................................81
11.9
Publication of Results ........................................................................................82
11.10 Disclosure and Confidentiality ...........................................................................82
11.11 Discontinuation of Study....................................................................................82
11.12 Subject Insurance and Indemnity........................................................................83
12
APPENDICES.............................................................................................................84
LIST OF IN-TEXT TABLES
Table 1
Calculated Safety Margins for Multiple Ascending Doses  (Revised 
per Amendment 01)................................................................................44
Table 2
Predicted Exposure Margins for Multiple Ascending Doses  (Revised 
per Amendments 01 and 02)...................................................................45
Table 3
Clinical Laboratory Tests........................................................................56
Table 4
Schedule of Procedures/Assessments in Study E2814-G000-103:  
Cohort A (Revised per Amendments 01, 02, 03, and 04).........................60
Table 5 
Schedule of Procedures/Assessments in Study E2814-G000-103:  
Cohort B  (Revised per Amendments 03 and 04) ....................................64


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LIST OF IN-TEXT FIGURES
Figure 1 
Study Design for the Open-Label, Phase 1b/2 Study Cohort A  
(Revised per Amendments 01 and 02) ....................................................35
Figure 2 
Study Design for the Open Label, Phase 1b/2 Study Cohort B  
(Revised per Amendment 03) .................................................................35
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................85


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AD
Alzheimer’s disease
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
APP
amyloid precursor protein
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating – Sum of Boxes 
COVID-19
coronavirus 2019
CRA
clinical research associate
CRF
Case Report Form
CRO
contract research organization
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse event
DIAD
Dominantly Inherited Alzheimer’s Disease
DIAN-TU
Dominantly Inherited Alzheimer Network-Trial Unit
FAS
Functional Assessment Scale
FCSRT
Free and Cued Selective Reminding Test
GDS
Geriatric Depression Scale 
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
ICF
informed consent form


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Abbreviation
Term
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
mAb
monoclonal antibody
MAC-Q
Memory Assessment Questionnaire
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
MTBR
microtubule binding region
NFT
neurofibrillary tangles
NOAEL
no observed adverse effect level
NPI-Q
Neuropsychiatric Inventory–Questionnaire
PD
Pharmacodynamic 
PET
Positron Emission Tomography
PGx
pharmacogenomic
PI
principal investigator
PK
pharmacokinetic
PSEN1
presenilin 1
PSEN2
presenilin 2
PT
Preferred term
Q4W
every 4 weeks
sAD
sporadic AD
SAD
single ascending dose 
SAE
serious adverse event


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Abbreviation
Term
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
TE
target engagement
TEAE
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory value
THC
tetrahydrocannabinol
tmax
time to reach maximum drug concentration
t-tau
total tau
ULN
upper limit of normal
WAIS-R
Wechsler Adult Intelligence Scale-Revised
WMS-R
Wechsler Memory Scale-Revised


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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 
(GCP), 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 (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
Where appropriate, at the end of the study, the sponsor should notify the IRB/IEC and 
Competent Authority 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 Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki 2013 


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
ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products/ICH/135/95) 
of the European Agency for the Evaluation of Medicinal Products, Committee for 
Proprietary Medicinal Products, ICH

Title 21 of the United States Code of Federal Regulations regarding clinical studies, 
including Part 50 and Part 56 concerning informed subject consent and IRB regulations 
and applicable sections of US 21 Code of Federal Regulations 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 guardian, in accordance with applicable professional standards and local 
laws/regulations or legally acceptable representative, 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.
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 
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 4 or more investigational sites in the United States (US) and 
United Kingdom (UK).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization (CRO) are listed in the Investigator 
Study File provided to each site.
7
INTRODUCTION
7.1
Pathology of Alzheimer’s Disease
Tau proteins, which belong to the family of microtubule-associated proteins, are mainly 
expressed in neurons and found in the axons and dendrites.  Tau proteins play an important 
role in the assembly of tubulin monomers into microtubules to constitute the cytoskeleton 
and serve as tracks for axonal transport.  Tau proteins are translated from a single gene 
located on chromosome 17, with alternative mRNA splicing leading to the formation of 
6 different tau isoforms, of which 5 are found in the human adult brain.  The isoforms differ, 
with having either 3 (R1, R3, and R4) or 4 (R1–R4) repeat-regions in the 
carboxy(C)-terminal part and variable occurrence of microtubule binding region (MTBR).  
The amino(N)-terminal domain, which establishes links between microtubules and other 
parts of the cytoskeleton, or the plasma membrane, has a variable occurrence of 0, 1, or 
2 inserts of 29 amino acids (Falcon, et al., 2015).
Tau proteins are the key constituent of intracellular fibrillar lesions described in Alzheimer's 
disease (AD) and other neurodegenerative disorders, referred to as tauopathies.  Aggregation 
of hyperphosphorylated tau into insoluble paired helical filaments that accumulate in nerve 
cells is a critical process in the formation of neurofibrillary tangles (NFTs), which is a 
hallmark pathological finding in AD, a secondary tauopathy (Fitzpatrick, et al., 2017).  NFTs 
are also a pathological finding in primary tauopathies, such as Frontotemporal Lobar 
Degeneration linked to chromosome 17, Corticobasal Degeneration, Pick’s disease, 
Progressive Supranuclear Palsy, and Argyrophilic grain disease, among others.  Recent in 
vitro and in vivo research on the development of paired helical filaments and NFTs has 
shown that the pathophysiological tau process appears to be initiated by the occurrence of 
extracellular tau seeds.  These small soluble tau seeds trigger the spread of tau pathology 
across the brain, possibly in a transynaptic manner, inducing the formation of intracellular 
insoluble tau aggregates, thereby driving the development of NFT pathology (Goedert and 
Spillantini, 2017, Noble, et al., 2013, and von Bergen, et al., 2000).  In AD, NFTs occur in a 
neuroanatomically characteristic pattern of increasing severity, generally defined according 
to the Braak stages I to VI, which correlate well with progressive neuronal loss and clinical 
decline.  Consequently, selective targeting and removal of tau seeds is expected to stop or 
slow down disease progression in tauopathy.


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7.2
Compound Overview
The Therapeutic Innovation Group compound “C”-E2814 is a novel immunoglobulin G 
subclass 1a monoclonal antibody (mAb) that binds with high affinity to 2 epitopes in the 
4R region and one epitope in the 3R region of tau.  Critically, E2814 has been shown to bind 
to the MTBR, a region on tau that is found in the vast majority of tau species and considered 
to be required for tau seeding to occur.  E2814 has been shown to inhibit tau aggregation in 
vitro, while the murine form of E2814 (7G6) has shown the ability to reduce the transmission 
of tau species in vivo, even in a model containing just 1 of the 2 binding sites normally found 
in the 4R isoform of the tau protein (Roberts, et al., 2020).  The proposed mechanism for 
drug effect in humans is that E2814 will bind to the assumed low amounts of extracellular 
MTBR-containing tau and thereby inhibit further tau aggregation and accelerate its clearance, 
such as mAb mediated uptake and phagocytosis in microglia.
The target clinical indication for E2814 is AD, which represents the most common tauopathy 
with a significant global disease burden, exerting a devastating effect on patients and their 
families and having a considerable impact on healthcare systems.  However, development of 
highly effective AD treatments has been hampered by the lack of surrogate biomarkers, slow 
course of cognitive and clinical decline, variability in clinical phenotype, and variability 
when measuring cognition and functional impairments in AD.  These challenges are 
especially difficult since validated diagnosis of AD in the absence of symptoms has not yet 
been achieved.  Prevention trials thus must be long and large due to inability to predict if and 
when cognitive symptoms will start, lack of functional impairment, and difficulties 
identifying an at-risk study population prior to symptomatic cognitive decline.
In order to address key AD prevention trial design challenges through utilizing a population 
almost certain to develop AD – the Dominantly Inherited AD (DIAD) population, the 
Dominantly Inherited Alzheimer Network-Trial Unit (DIAN-TU) designed and executed a 
pioneering prevention trial for the DIAD population (Bateman, et al., 2017).  The DIAD 
population represents a unique group for study since the genetic mutations in these 
individuals are thought to underlie the pathophysiologic changes inherent in AD.  In addition, 
the impact of age-related changes on cognitive function and brain pathology are minimized 
since cognitive impairment occurs at a younger and predictable age based on family history.  
Changes in cognitive, clinical, biochemical, and structural measures in DIAD are similar to 
sporadic AD (sAD), suggesting that a common pathophysiology exists between DIAD and 
sAD. Therefore, treatment trials in DIAD are likely to provide further insights into 
underlying mechanisms of the common pathophysiology.
Regarding tau pathology for the comparison between DIAD and sAD, the distribution of 
NFT pathology appears similar between DIAD and sAD and the molecular and 
3-dimensional structure of the tauopathies are identical (Fitzpatrick, 2017).  Further, recent 
studies in the DIAN consortium have demonstrated similar distributions of tau Positron 
Emission Tomography (PET) signals in DIAD and sAD.  Thus, the distribution and type of 
tau pathology among DIAD and sAD are analogous.  This evidence strongly suggests that the 
temporal order and progression of pathophysiological, cognitive, and clinical changes are 


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shared in DIAD and sAD.  Therefore, DIAD presents a unique opportunity to examine 
experimental disease modifying therapies for AD.  Patients can be identified for whom the 
likelihood of future dementia is essentially certain and therapy can be initiated at predictable 
times in relation to measurable disease biomarkers.  Moreover, in light of the diagnostic 
reliability and consequent population homogeneity, such studies require fewer patient 
participants and shorter total study lengths relative to trials in sAD.
The findings from the previous randomized clinical trials for anti-amyloid antibodies in the 
DIAN-TU platform are viewed as the supportive reason to explain testing tau-based agents in 
DIAD subjects and may represent the best possibility for measurable benefit in either 
biomarker outcomes or cognitive decline.  Given this situation, Eisai’s anti-tau antibody 
(E2814) has been selected as one candidate for the next step of the DIAN-TU Trials.
7.3
Study Rationale
The proposed study is an open-label Phase 1b/2 study to evaluate the safety and target 
engagement (TE) of 2 different doses of E2814 on MTBR-tau species in cerebrospinal fluid 
(CSF) in subjects with DIAD and exhibiting mild to moderate cognitive impairment. This 
study will target individuals who are known to have a disease-causing mutation confirmed by 
the genetic testing.  The study will also assess the pharmacokinetic (PK), immunogenicity, 
and other pharmacodynamic (PD) effects of E2814.  No formal sample size calculations have 
been performed.  For this Phase 1b/Phase 2 study, up to 8 subjects in Cohort A and up to 
5 subjects in Cohort B are considered adequate to evaluate the initial safety and PK in 
symptomatic DIAD subjects and to establish evidence of TE.  (revised per Amendment 03)
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives of the study are:  

To assess the safety and tolerability of intravenous (IV) infusions of E2814 in subjects 
with DIAD

To evaluate TE of E2814 on MTBR-tau species in CSF in subjects with DIAD
8.2
Secondary Objectives
The secondary objectives of the study are:  

To assess the PK of E2814 in serum, plasma, and CSF

To assess the immunogenicity (production of anti-E2814 antibody) of E2814

To assess the effect of E2814 on CSF, blood, and imaging biomarkers






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Screening will occur between Day –60 and Day –2.  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.  Screening assessments will include tau PET, 
amyloid PET, and safety magnetic resonance imaging (MRI) and genetic testing to confirm 
mutation status.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.
Cohort B Screening Period (revised for Amendment 03)
Screening will occur between Day -60 and Day -2. The purpose and assessments are the 
same as for the remainder of the subjects except that amyloid PET will not be done in 
Cohort B subjects.
9.1.2
Treatment Phase
During the Cohort A Phase 2 and Cohort B Treatment Periods, infusions will take place in 
the clinic.  When the process for home infusion is established, and if allowed and conducted 
according to local guidelines, the investigator may assess for an individual subject if home 
infusions are suitable according to the following guidelines:  If a subject has shown 
acceptable tolerability for the infusions, is considered by the investigator to be at low risk of 
developing AEs related to study drug infusion that may require acute medical treatment, and 
has shown no clinically significant findings on other safety measures related to study drug 
infusion during the Cohort A Phase 1b Treatment Period or the first month or first dose of 
Cohort B treatment, he or she may be allowed to receive infusions at home keeping in 
accordance with the required infusion schedule, depending on the feasibility for blood 
sampling or cognitive assessments on the scheduled visits.  (revised per Amendment 03)
9.1.2.1
Cohort A
9.1.2.1.1
PHASE 1B TREATMENT PERIOD
The Phase 1b Treatment Period will initially allow 8 subjects to receive open-label treatment 
with 3 IV infusions of 750 mg E2814 every 4 weeks (Q4W) over 12 weeks.  Subjects will 
check into the clinic on the day before dosing but will not be required to stay in the clinic 
overnight on Day -1 to Day 2, they may instead stay overnight at a nearby hotel and return to 
the clinic the next day.  In addition, subjects will have outpatient visits on Days 15, 29, and 
57.  On conclusion of the Phase 1b Treatment Period, on Day 84, subjects will check into the 
clinic and will undergo safety assessments.  Subjects will not be required to stay in the clinic 
overnight on Day 84 to Day 86, they may instead stay overnight at a nearby hotel and return 
to the clinic the next day.  A CSF sample will be collected for assessment of TE and CSF 
concentrations of E2814 on Day 1 and Day 84.  Subjects will then progress to the Phase 2 
Treatment Period. Subjects who withdraw from the Phase 1b Treatment Period for reasons 
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concentrations of E2814 in postdose samples will also be assessed.  Subjects will also 
undergo safety MRI, tau PET scans, and cognitive assessment at Visit 2, Week 24, and the 
End of Study/Early Termination Visit.  For subjects who discontinue early, early termination 
CSF collection and tau PET scan will be performed, unless these assessments were 
performed within the previous 3 months.
9.1.2.3
Follow-Up Period
The Follow-up Period will follow all subjects for a period of 12 weeks after the last dose for 
safety.
9.2
Discussion of Study Design, Including Choice of Control Groups
The study will consist of 2 cohorts (A and B)  (revised per Amendment 03):  
Cohort A will consist of 2 phases:
1. The Phase 1b component of Cohort A will evaluate IV infusions of 750 mg E2814 (an 
intermediate dose of E2814) Q4W for 3 doses (12 weeks) to assess safety, tolerability, 
TE, PK, and immunogenicity of E2814.
2. The Phase 2 component of Cohort A will be initiated to receive a further 96 weeks of IV
E2814 at an initial dose of 1500 mg Q4W for at least 3 doses (12 weeks), followed by 
3000 mg Q4W for at least 3 doses (12 weeks), followed by 4500 mg Q4W for the 
remaining weeks. (revised per Amendments 01 and 02) Subjects must complete the 
Phase 1b component before they enter the Phase 2. 
Cohort B will receive IV E2814 at a dose of 3000 mg Q4W for up to 52 weeks.  (revised per 
Amendment 03)
In both Cohorts, pharmacogenomic (PGx) samples will be collected and may be used to 
explore heterogeneity in clinical features of disease including differences in baseline 
characteristics as well as PK, PD, and/or safety-related outcomes.  For this compound, there 
is no expectation that any of these endpoints will be impacted by PGx variability on the 
absorption, distribution, metabolism, and elimination of E2814.  PGx samples from this study 
may be used for future exploratory analyses which are not limited to this protocol or project.  
Findings may also be used, after pooling with samples across studies or projects as 
appropriate, for identification and validation of new drug targets and for potential diagnostic 
development.  (revised per Amendment 03)
9.3
Selection of Study Population
Up to 13 subjects (up to 8 subjects in Cohort A and up to 5 subjects in Cohort B) will be 
enrolled at approximately 4 or more sites in the US and UK.  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.  (revised per Amendment 03)  








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28. Visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately.
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.
9.4
Treatments
9.4.1
Treatments Administered
Cohort A:  

Phase 1b:  750 mg E2814 administered as a 1-hour intravenous infusion (maximum 
infusion time 2 hours, if needed) Q4W. Duration of treatment will be 12 weeks.

Phase 2: 1500 mg or 3000 mg E2814 administered as a 1-hour intravenous infusion 
(maximum infusion time 2 hours, if needed) Q4W for at least 3 doses (12 weeks)
followed by 3000 mg Q4W for at least 3 doses (12 weeks), then 4500 mg Q4W for the 
remaining weeks. The 4500 mg doses will be administered as a 2-hour intravenous 
infusion (maximum infusion time 4 hours, if needed) Q4W. Total duration of treatment 
will be 96 weeks.  (revised per Amendments 01, 02, and 03)
Cohort B:  3000 mg administered as a 1-hour IV infusion (maximum infusion time 2 hours, 
if needed) Q4W. (revised per Amendment 04)  Duration of treatment will be 52 weeks.  
(revised per Amendment 03)
The duration of the Post-Treatment Follow-up Period in both cohorts will be 12 weeks.  
(revised per Amendment 03)
9.4.2
Identity of Investigational Product
Investigational products, ie, test drug will be supplied by the sponsor in labeled containers.
9.4.2.1
Chemical Name of E2814

Test drug code:  E2814

Generic name:  Not available.

Chemical name:  Not applicable


9.4.2.2
Comparator Drug
Not applicable.
CCI




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One of the primary objectives of this study is to confirm TE in subjects with DIAD.  
Furthermore, this study is designed to investigate whether the safety profile of E2814 in 
subjects with DIAD is similar to the safety profile in healthy subjects in Study 001.
CCI


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9.4.5
Selection and Timing of Dose for Each Subject
The 750, 1500, and 3000 mg doses will be administered as a 1-hour IV infusion (maximum 
infusion time 2 hours, if needed) Q4W.  The 4500 mg doses will be administered as a 2-hour 
IV infusion (maximum infusion time 4 hours, if needed) Q4W.  (revised per Amendments
01, 02, and 03)
9.4.6
Blinding
This study will not be blinded.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the counter medications and vaccines) or therapy 
administered to the subject during the study will be recorded.
Stable doses of medication(s) for the treatment of non-excluded medical condition(s) will be 
permitted provided the dose has been stable for at least 30 days prior to Screening, if they are 
free of any clinically important side effects attributable to the drug.
Stable doses of cholinesterase inhibitors and/or memantine will be permitted if they have 
been taking these medications for at least 90 days prior to Screening and has been on a stable 
dose for at least 60 days prior to Screening.
CCI


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Flu, shingles, pneumococcal and hepatitis B, and other vaccines can be administered at least 
2 weeks before the 1st administration of the study drug in Phase 1b Treatment Period.  Once 
study drug dosing initiates, no vaccines should be administered before the 3rd infusion. 
Thereafter, the vaccines can be administered during Phase 2 Treatment Period and Follow-up 
Period. Vaccination should be timed such that it will be administered at least 7 days after the 
previous infusion and at least 7 days before the next infusion of the study drug.  (revised per 
Amendment 01)
COVID-19 vaccination will not be allowed from 7 days before dosing and until 7 days after 
each dose.  Where possible, subjects should be encouraged to receive their full course of 
COVID-19 vaccination prior to 7 days before initiation of dosing in this study.  (revised per 
Amendment 01)
The use of marijuana (including products containing tetrahydrocannabinol [THC]) is allowed 
during the study if the investigator confirms that there is no suspected abuse or dependency 
related to marijuana and THC use will not prevent the subject from performing psychometric 
tests accurately. (revised per Amendment 02)
The following concomitant drugs and therapies are not permitted before Screening and until 
the last visit during the Treatment Period: 
a.
Immunoglobulin therapy and biologic drugs are not permitted within 6 months before 
Screening and until the last visit during the Treatment Period
b. Systemic immunosuppressive or immunomodulatory drugs are not permitted for a period 
of 5 half-lives or 60 days (whichever is longer) before Screening and until the last visit 
during the Treatment Period
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 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 
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
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 PI and all subinvestigators listed on Form FDA 1572
or Investigator and Site Information Form

A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae

A signed and dated clinical studies agreement.  

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies 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/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies 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/study supplies and empty and partially 
empty containers from used study drugs/study supplies are to be returned to the investigator 
by the subject and, together with unused study drugs/study supplies 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/study supplies 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/study supplies to the central or local depot(s).  Approval 
for destruction to occur at the site must be provided by the sponsor in advance.  Upon 
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documentation procedures by the sponsor’s personnel, study drugs/study supplies 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/study supplies may be removed from the site and hand delivered 
to the central or local depot by sponsor representatives.  Where study drugs/study supplies 
are approved for destruction at the site, destruction will occur following the site’s standard 
procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Screening Assessments
Screening assessments will be conducted as specified in the Schedule of 
Procedures/Assessments (Table 4 or Table 5).  Assessments scheduled to be conducted at the 
Screening Visit (Visit 1) only, are described below (Sections 9.5.1.1.1 through 9.5.1.1.4).  
(revised per Amendment 03)  
9.5.1.1.1
DEMOGRAPHY 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes age, sex, race/ethnicity.  (revised per Amendment 01)
9.5.1.1.2
MEDICAL HISTORY
Medical and surgical history 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 Case Report Form (CRF).
9.5.1.1.3
VIRAL TESTS
A (6 mL) sample of blood will be taken for hepatitis B core antibody (HBcAb), hepatitis B 
surface antigen (HBsAg), hepatitis C virus antibody (HCVAb) and HIV tests at the Screening 
Visit.  Test dates and results will be recorded in the medical records at the study site.
9.5.1.1.4
DRUG, COTININE, AND ALCOHOL TESTS
Urine Drug and Cotinine Test
A sufficient urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 4 or Table 5).  This sample will be tested for 
common drugs of use/abuse:  eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, 
nicotine/cotinine, opioids (as a group), benzodiazepines, barbiturates, and amphetamines.  
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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.  Refer to Section 9.5.4.1
for the time period after the end of treatment for serious adverse event (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 AE CRF. 
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 clinical assessment of 
suicidality, 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.
All AEs must be followed for 16 weeks 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.  (revised per Amendment 01)
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 CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
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


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
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 CRF 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
A 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 AE 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.
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, 
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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 CRF 
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 “AE” (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
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the 1st report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.4.3
STUDY-SPECIFIC ADVERSE EVENTS
The study-specific events, infusion reaction, should always be considered AEs and reported 
on the AE CRF and on the event-specific CRFs designed to collect additional information on 
specific events.
Infusion Reactions
Any infusion-related reaction should be graded and managed according to the recent 
Common Terminology Criteria for Adverse event (CTCAE), Version 5.0, grading of 
allergic/hypersensitivity reactions/cytokine release, as follows:

Grade 1:  mild reaction, infusion interruption not indicated, systemic intervention not 
indicated

Grade 2:  oral intervention indicated (eg, antihistamines, nonsteroidal anti-inflammatory 
drugs, corticosteroids)

Grade 3:  prolonged reaction or recurrence of symptoms, bronchospasm, hospitalization 
indicated for clinical sequelae, IV intervention indicated

Grade 4:  life-threatening consequences; urgent treatment needed

Grade 5:  death
Infusion reactions of any grade outlined above (Grade 1 to 5) should be reported as AEs of 
special interest.


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If a Grade 2 infusion reaction occurs, the infusion may be stopped (as deemed appropriate by 
the investigator) and the subject treated with antihistamines, corticosteroids, 
anti-inflammatory drugs, or other medications as medically indicated.
If a Grade 3 or higher infusion reaction occurs, the infusion should be immediately stopped 
and the subject should be treated with antihistamines, corticosteroids, anti-inflammatory 
drugs, IV fluids, or other medications and treatment as medically indicated.
9.5.1.4.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, clinical chemistry, and 
urinalysis, are summarized in Table 3.  Subjects should be in a seated or supine position 
during blood collection.  The Schedule of Procedures/Assessments (Table 4 or 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.  (revised per Amendment 03)
Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), fibrinogen, prothrombin time, aPTT, INR
Clinical 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
Blood chemistry
Free T3, free T4, TSH, Vitamin B12, methylmalonic acid, 
C-reactive protein
Other
Albumin, total cholesterol, globulin, glucose, lactate 
dehydrogenase, inorganic phosphorus, total protein, protein 
fraction, triglycerides, uric acid, HbA1c, hepatitis viral screen 
(HBcAb, HBsAg, HCVAb), HIV
Urinalysis
Glucose, ketones, occult blood, pH, protein, sediment (RBCs, 
WBCs, bacteria, casts, crystals, epithelial cells), specific gravity
HbA1c levels and viral screen will be done at Screening only. 
Total fibrinogen levels (measured in plasma using immunological methods) and functional fibrinogen 
(measured in plasma using the Clauss method) will be determined. 
aPTT = activated partial thromboplastin time, HbA1c = glycosylated hemoglobin, HBcAb = hepatitis B core 
antibody, HBcAg = hepatitis B core antigen, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C 
virus antibody, HIV = human immunodeficiency virus, INR = international normalized ratio, RBC = red 
blood cell, WBC = white blood cell.
Clinical laboratory tests will be performed by a central laboratory.  All blood and urine 
samples will be collected and sent to the central laboratory on the day of collection unless 


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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.  Local 
laboratories will perform tests to qualify subjects for entry into the study.  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 CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the AE CRF [see 
Section 9.5.4.3.2]).
9.5.1.4.5
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), height (cm) and
weight (kg) will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 4 or Table 5) by a validated method.  BP and pulse will be 
measured after the subject has been supine or semi-supine for 5 minutes.  All BP 
measurements should be performed on the same arm, preferably by the same person.  
(revised per Amendment 03)  
9.5.1.4.6
PHYSICAL EXAMINATIONS
Comprehensive and abbreviated physical examinations will be performed as designated in 
the Schedule of Procedures/Assessments (Table 4 or Table 5).  Documentation of the 
physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.  Changes from Screening physical examination findings that meet the 
definition of an AE will be recorded on the AEs CRF (see Section 9.5.1.4.1).  (revised per 
Amendment 03)
Comprehensive Physical Examination
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well. A urogenital examination will only be required in the presence 
of clinical symptoms related to this region.
Abbreviated Physical Examination
Health status will be assessed by brief evaluation of the head, eyes, ears, nose, throat, 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 4 or Table 5).  (revised per Amendment 03)






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9.5.2.2
Description of Procedures/Assessments Schedule
See Section 9.5.1 for a full description of the procedures and assessments to be performed 
during this study. 
See Table 4 and Table 5 for the timing of the procedures and assessments to be performed 
during the study. A window of ±7 days will be permitted for all visits after Visit 2.  The visit 
windows should be calculated from the day of 1st dose (Day 1).  If a permitted visit window 
is used, every effort should be made to bring the subject back in line with the prespecified 
visit schedule at subsequent visits.  Assessments for study visits that require PET, MRI, 
and/or cognitive assessments may be completed over several days if needed provided all 
assessments are completed within the visit window.  (revised per Amendments 01, 02, and 
03)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in Phase 1b/Phase 2 
studies.
The safety assessments to be performed in this study, including hematology analyses, clinical
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard 
evaluations to ensure subject safety.
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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 24 hours from 
the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected for 100 days after the subject’s 
last dose.  All SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any SAE judged by the investigator to be related to the study treatment 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.


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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 
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 16 weeks 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 
16 weeks of last study treatment), or any exposure to study drug through breastfeeding 
during study treatment or within 16 weeks 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 SAEs [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.  A subject who 
becomes pregnant may remain in the study if the investigator judges that the potential benefit 
to the subject outweighs any potential risk to the subject or the fetus and the subject gives 
informed consent for the further participation.
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
AEs 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:


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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 AE CRF and also reported using the procedures detailed in Reporting of SAEs 
(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 criteria, it must 
still be reported using the SAE form and in an expedited manner but should be noted as 
nonserious on the SAE form and the AE CRF.
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 AE CRF and reported using the procedures 
detailed in Reporting of SAEs (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) lab value 
that is greater than or equal to 3× the upper limit of normal (ULN) or if elevated greater 
than the ULN at baseline, then 3× the baseline for the subject
AND

Elevated total bilirubin lab value that is greater than or equal to 2× the ULN or if elevated 
greater than the ULN at baseline, then 1.5× the baseline for the subject
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.  (revised per Amendment 01)


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9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (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
AEs will be reported by the sponsor or a 3rd party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  
The format of these reports will be dictated by the local and regional requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 4).
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, inadequate therapeutic effect, progression 
of disease, withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In 
addition to the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation.  Study disposition information will be collected on the Subject Disposition 
CRF.
Subjects who withdraw from the Phase 1b Treatment Period for reasons other than safety 
may be replaced.  A subject removed from the study for any reason during the Phase 2
Treatment Period may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.


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9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 or Investigator and Site Information Form must sign the completed CRF to attest to its 
accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to 3rd parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP).


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9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINTS

Incidence of treatment-emergent adverse events (TEAEs) and SAEs, laboratory 
parameters, vital signs, and ECGs

Change from baseline in CSF free and bound MTBR-tau and total MTBR-tau at 
12 weeks in Cohort A  (revised per Amendment 03)
9.7.1.1.2
SECONDARY ENDPOINTS

Serum and plasma PK parameters following dosing on Days 1 and 85

CSF E2814 concentrations

Serum (or plasma) anti-E2814 antibody concentration

Change from baseline in CSF and/or plasma biomarkers including total tau (t-tau) and 
phosphorylated tau biomarkers

Change from baseline in tau PET signal
9.7.1.1.3
EXPLORATORY ENDPOINTS 
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of all allocated subjects who received at least 1 dose of 
study drug.  At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at 
least 1 dose of study treatment is required for inclusion in the analysis of each specific 
parameter.  To assess change from baseline, a baseline measurement is also required.  This is 
the analysis population used for all safety analyses which will be based on as-treated 
principle.  (revised per Amendment 01)
The PK Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had sufficient PK data to derive at least 1 PK parameter.
The PD Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had sufficient PD data to derive at least 1 PD parameter.
CCI


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The definition of these analysis sets is the same for both the Phase 1b and Phase 2 Treatment 
Periods; actual determination of these analysis sets will be made separately for each study
period.
9.7.1.3
Subject Disposition
The number of subjects administered each dose of E2814 along with the number in each of 
the analysis sets will be presented overall and by cohort.  (revised per Amendment 03)
The number of subjects completing the study will be presented overall and by cohort.  
(revised per Amendment 03)
Subjects who prematurely terminate their participation in the study will be summarized by
their primary reason for study termination.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized by dose using descriptive statistics overall and by cohort.  Continuous 
demographic and baseline variables include age, height and weight; categorical variables 
include sex, age group, and race.  (revised per Amendment 03)
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded using the World 
Health Organization Drug Dictionary (Sep 2020).  Prior medications will be defined as 
medications that stopped before the 1st dose of study drug.  Concomitant medications will be 
defined as medications that (1) started before the 1st dose of study drug and were continuing 
at the time of the 1st dose of study drug, or (2) started on or after the date of the 1st dose of 
study drug up to 100 days after the subject’s last dose.  All medications will be presented in 
subject data listings.
9.7.1.6
Efficacy Analyses
Change from baseline in cognitive assessments will be summarized by visit.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK analysis will be performed on the PK Analysis Set.  Serum and plasma 
concentrations of E2814 will be tabulated by nominal sampling time and summarized by 
dose using summary statistics in Cohort A and Cohort B.  Serum and plasma concentration-
time profiles will be plotted.  (revised per Amendment 03)


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Serum and plasma E2814 PK parameters will include (but not be limited to) Cmax, time to 
reach maximum drug concentration (tmax) and area under the concentration-time curve from 
zero time to the end of the dosing interval (AUC(0-672h)) on Days 1 and 85 in Cohort A.  
(revised per Amendment 03)
An integrated population analysis of E2814 PK will be performed by pooling data from 
Cohort A and Cohort B, and from all available studies.  For population PK, the details will be 
described in a separately prepared analysis plan and its report, and the results will be 
provided in a separate report.  (revised per Amendment 03)  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The PD Analysis Set will be used for both the listings and summaries of all biomarker CSF 
and plasma measurements (ie, free and bound MTBR-tau, total-MTBR-tau, and other 
biomarker assessments as data permit).  Biomarker measurements (fluid and imaging) and 
change from baseline will be summarized by time point and dose and presented graphically.
These analyses will be done for CSF, plasma and serum.  Dose-response relationships will be 
evaluated.
9.7.1.7.3
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
The relationship between PK and PD will be evaluated by visual inspection using plots.  This 
may include but is not limited to the graphical exploration of the PK/TE relationship between 
E2814 concentrations and MTBR-tau binding in CSF.
PGx analyses may be performed and reported separately.  Details of these analyses will be 
described in a separate analysis plan, and the results will not be included in the clinical study 
report.
9.7.1.8
Safety Analyses
Evaluation of safety will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include AEs, clinical laboratory results, vital signs, ECGs, C-SSRS, and physical 
examinations.  Safety data from the Phase 1b period of Cohort A will be summarized 
separately from the Phase 2 Treatment Period of Cohort A and Cohort B.  TEAEs will be 
summarized by dose.  (revised per Amendment 03)
Descriptive statistics (eg, mean, SD, median, minimum, and maximum for continuous 
variables, and the number and percent for categorical variables) of the laboratory, vital signs, 
and ECGs, and changes from baseline will be evaluated by dose.
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure to study drug will be presented in subject data listings.


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9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA) (Version 21.0 or higher).
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 dose.  The incidence of TEAEs will be reported as the 
number (percentage) of subjects with TEAEs by system organ class (SOC) and preferred 
term (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 will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each dose.  A subject data listing of all AEs leading to death will 
be provided.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each dose.  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 dose. A subject data listing of all 
AEs leading to discontinuation from study drug will be provided.


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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.4.4, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and dose using descriptive statistics.  
Qualitative parameters listed in 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 nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the Treatment Period.
Appendix 1 (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.  A listing of 
subjects with markedly abnormal laboratory values will be generated, which will be ordered 
by dose and subject.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, body temperature, weight) and changes from baseline will be presented by 
dose and visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) by dose and visit to 
end of treatment. 
9.7.1.8.6
OTHER SAFETY ANALYSES
Subject data listings of viral tests, pregnancy tests, urine drug, breath alcohol and cotinine 
tests will be provided.


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9.7.1.9
Other Analyses
The number (percentage) of subjects with positive and negative ADA and ADA titer 
categories (eg, >0, 5, 25, 125) by visit and dose will be summarized.  In addition, the 
correlation between ADA titer and PK profile will be evaluated using descriptive statistics 
and summary plots at a minimum.
Change from baseline in tau PET and amyloid PET (Cohort A only; revised per 
Amendment 04) will be summarized by visit.
9.7.2
Determination of Sample Size
No formal sample size calculations have been performed.  For this Phase 1b/Phase 2 study, 
up to 8 subjects in Cohort A and up to 5 subjects in Cohort B are considered adequate to 
evaluate the initial safety and PK in symptomatic DIAD subjects and to establish evidence of 
TE.  (revised per Amendment 03)
9.7.3
Interim Analysis
Not applicable.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the 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
Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The 
DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease 
progression model. Alzheimers Dement. 2017;13(1):8-19.
Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, et al. Conformation 
determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 
2015;290(2):1049-65. 
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, et al.  Cryo-EM 
structures of tau filaments from Alzheimer's disease. Nature. 2017;547(7662):185-90.
Goedert M, Spillantini MG.  Propagation of Tau aggregates.  Mol Brain. 2017;10(1):18.


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Noble W, Hanger DP, Miller CCJ, Lovestone S. 2013.  The Importance of Tau 
Phosphorylation for Neurodegenerative Diseases. Front Neurol. 2013;4:83.
Roberts M, Sevastou I, Imaizumi Y, Mistry K, Talma S, Dey M, et al.  Pre-clinical 
characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat 
domain of tau for passive immunotherapy in Alzheimer's disease.  Acta Neuropathol 
Commun. 2020;8(1):13.
von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly 
of tau protein into Alzheimer paired helical filaments depends on a local sequence motif 
((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A.  
2000;97(10):5129-34.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and 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 interactive voice and web response 
system, x-rays, and other imaging reports (eg, sonograms, computerized tomography 
scans, magnetic resonance images, radioactive images, ECGs, rhythm strips, EEGs, 
polysomnographs, pulmonary function tests) regardless of how these images are stored, 
including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source

Electronic Patient-Reported Outcome by self-reported measures
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents. For 
the following item(s), the data recorded directly on the CRF are to be considered source data:  

Reasons for discontinuation of study treatment

Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome)

Reasons for dose modification

Indication for prior/concomitant medication


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
Sampling times for drug concentrations

Sampling times for clinical laboratory tests
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites), Investigator and Site Information Form (for 
non-US sites), ICFs, and IRB/IEC correspondence.  In addition, the sponsor will send a list 
of treatment codes by study subject to the investigator after the clinical database for this 
study has been locked.  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 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the PI (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 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.


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11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension. The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.


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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
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), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: 27 Nov 2017.


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PROTOCOL SIGNATURE PAGE
Study Protocol 
Number:
E2814-G000-103
Study Protocol Title:
An Open-Label Phase 1b/2 Study to Assess Safety and Target 
Engagement of E2814 in Subjects with Mild to Moderate 
Cognitive Impairment due to Dominantly Inherited 
Alzheimer’s Disease 
Investigational Product 
Name:
E2814 
IND Number
139378
EudraCT Number
2020-005728-12
SIGNATURES
Authors:
 
Study Director and Medical Monitor 
 
Eisai Inc
Date
Clinical Pharmacologist
Eisai Ltd.
Date
Primary Statistician 
Eisai Ltd
Date
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2814-G000-103
Study Protocol Title:
An Open-Label Phase 1b/2 Study to Assess Safety and Target 
Engagement of E2814 in Subjects with Mild to Moderate 
Cognitive Impairment due to Dominantly Inherited 
Alzheimer’s Disease 
Investigational Product
Name:
E2814 
IND Number
139378
EudraCT Number
2020-005728-12
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 GCP 
guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
.

SAP_001.pdf: 
Statistical Analysis Plan
E2814-G000-103
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Page 1 of 22
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2814-G000-103
Study Protocol 
Title:
An Open-Label Phase 1b/2 Study to Assess Safety and Target 
Engagement of E2814 in Subjects with Mild to Moderate Cognitive 
Impairment due to Dominantly Inherited Alzheimer’s Disease 
Date:
23 July 2024
Version:
Final Version 1.0


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Eisai
Final (Version 1.0)
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS....................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................4
3
INTRODUCTION..............................................................................................6
3.1
Study Objectives.......................................................................................6
3.1.1
Primary Objectives..........................................................................6
3.1.2
Secondary Objectives ......................................................................6
3.1.3
Exploratory Objectives....................................................................6
3.2
Overall Study Design and Plan..................................................................6
4
DETERMINATION OF SAMPLE SIZE............................................................7
5
STATISTICAL METHODS...............................................................................7
5.1
Study Endpoints........................................................................................7
5.1.1
Efficacy Endpoints ..........................................................................7
5.1.2
Safety Endpoints .............................................................................7
5.1.3
Pharmacokinetic (PK) Endpoint(s) ..................................................7
5.1.4
Pharmacodynamic (PD) Endpoint(s)................................................7
5.2
Study Subjects ..........................................................................................8
5.2.1
Definitions of Analysis Sets.............................................................8
5.2.2
Subject Disposition..........................................................................8
5.2.3
Protocol Deviations.........................................................................8
5.2.4
Demographic and Other Baseline Characteristics.............................8
5.2.5
Prior and Concomitant Therapy.......................................................8
5.2.6
Treatment Compliance ....................................................................9
5.3
Data Analysis General Considerations.......................................................9
5.3.1
Pooling of Centers...........................................................................9
5.3.2
Examination of Subgroups...............................................................9
5.3.3
Handling of Missing Data, Dropouts, and Outliers...........................9
5.3.4
Other Considerations.......................................................................9
5.4
Efficacy Analyses .....................................................................................9
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses................................................................................10
5.5.1
Pharmacokinetic Analyses.............................................................10
5.5.2
Pharmacodynamic Analyses..........................................................10
5.5.3
Pharmacokinetic/Pharmacodynamic Analyses ...............................11
5.5.4
Pharmacogenomic/Pharmacogenetic and Other Biomarker Analyses
......................................................................................................11
5.6
Safety Analyses.......................................................................................11
5.6.1
Extent of Exposure........................................................................12
5.6.2
Adverse Events..............................................................................12
5.6.3
Laboratory Values.........................................................................13


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5.6.4
Vital Signs.....................................................................................13
5.6.5
Electrocardiograms........................................................................13
5.6.6
Other Safety Analyses ...................................................................13
5.7
Other Analyses........................................................................................13
5.8
Exploratory Analyses..............................................................................14
6
INTERIM ANALYSES....................................................................................14
7
CHANGES IN THE PLANNED ANALYSES .................................................14
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ..................14
8.1
Pharmacokinetic Data Handling..............................................................14
8.1.1
Lower Limit of Quantification of E2814 Serum and Plasma 
concentration.................................................................................14
8.1.2
BLQ Handling for Calculation of PK Parameters...........................14
8.1.3
BLQ Handling for Developing Concentration-Time Profiles .........14
8.1.4
Handling of Anomalous Concentration Values ..............................15
8.1.5
General Rules for Presentation of Drug Concentrations and PK 
Parameters.....................................................................................15
8.1.6
General Rules for Presentation of PD Parameters ..........................16
9
PROGRAMMING SPECIFICATIONS ............................................................16
10
STATISTICAL SOFTWARE...........................................................................17
11
MOCK TABLES, LISTINGS, AND GRAPHS.................................................17
12
REFERENCES.................................................................................................17
13
APPENDICES..................................................................................................18
13.1
Derivations for Clinical and Cognitive Assessments................................18
13.2
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results ....................................................................................................18


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
anti-drug antibody 
AE
adverse event
ALQ 
above the limit of quantification
ATC
anatomical therapeutic class
AUC(0-inf)
area under the concentration-time curve from zero time (pre-
dose) extrapolated to infinite time
AUC(0-t)
area under the concentration-time curve from zero time (pre-
dose) to time of last quantifiable concentration
BLQ
below the limit of quantification
BMI
body mass index
Cmax
maximum observed concentration
CRF
case report form
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DIAD
Dominantly Inherited Alzheimer’s Disease
ECG
electrocardiogram
LLOQ 
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MTBR
microtubule binding region
NAb
Neutralizing antibody
NCA-MNL
Eisai Non-compartmental Pharmacokinetic Analysis Manual
PT
preferred term
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
Q4W
every 4 weeks
SAP
statistical analysis plan
SD
standard deviation
SI
Système International
SOC
system organ class


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Abbreviation
Term
TE
target engagement
tmax
time at which the highest drug concentration occurs
t½
terminal elimination phase half-life
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value 
TLG
tables, listings, and graphs
ULOQ
upper limit of quantification
WHO
World Health Organization


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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 Protocol
E2814-G000-103 (Amendment 04).
3.1
Study Objectives
3.1.1
Primary Objectives
The primary objectives of the study were:  
•
To assess the safety and tolerability of intravenous (IV) infusions of E2814 in subjects 
with Dominantly Inherited Alzheimer’s Disease (DIAD)
•
To evaluate target engagement (TE) of E2814 on microtubule binding region
(MTBR)-tau species in CSF in subjects with DIAD
3.1.2
Secondary Objectives
The secondary objectives of the study were:  
•
To assess the pharmacokinetics (PK) of E2814 in serum, plasma, and cerebrospinal 
fluid (CSF)
•
To assess the immunogenicity (production of anti-E2814 antibody) of E2814
•
To assess the effect of E2814 on CSF, blood, and imaging biomarkers
3.1.3
Exploratory Objectives
The exploratory objectives of the study were:  
3.2
Overall Study Design and Plan
E2814-G000-103 was an open-label Phase 1b/2 study to evaluate the safety and TE of 
E2814 on MTBR-tau species in CSF following IV infusions of E2814 in DIAD subjects.  
Subjects in this study were confirmed mutation positive for genes known to be associated 
with DIAD.  The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid 
precursor protein (APP) that are associated with DIAD have very high penetrance (near 
100%).
The study consisted of 2 Cohorts (A and B).
Cohort A consisted of 2 phases:  A Pretreatment Phase consisting of a Screening Period 
and a Treatment Phase consisting of 3 periods:  1b, 2, and Follow Up.
CCI




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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of all allocated subjects who received at least 1 dose 
of study treatment. At least 1 laboratory, vital sign, or ECG measurement obtained 
subsequent to at least 1 dose of study treatment is required for inclusion in the analysis of 
each specific parameter. To assess change from baseline, a baseline measurement is also 
required. This is the analysis population used for all safety analyses which will be based 
on as-treated principle.
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 dose of 
test drug and had sufficient PK data to derive at least 1 PK parameter.
The Pharmacodynamic Analysis Set is the group of subjects who received at least 1 dose 
of study drug and had sufficient PD data to derive at least 1 PD parameter. 
The definition of these analysis sets is the same for both the Phase 1b (Cohort A) and 
Phase 2 (Cohort A and Cohort B) Treatment Periods; actual determination of these 
analysis sets will be made separately for each study period. Data from Cohort A and B 
will be presented combined. In other words, there will one Safety Analysis Set, one 
Pharmacokinetic Analysis Set and one Pharmacodynamic Analysis Set.
5.2.2
Subject Disposition
Reasons for screening failure will be summarized.
The number and percentage of subjects who completed the study will be summarized and 
the number who discontinued prematurely will be summarized by reason for 
discontinuation.
5.2.3
Protocol Deviations
Important protocol deviations will be presented as a listing.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be
summarized for all subjects using descriptive statistics. Continuous demographic and 
baseline variables include age, categorical variables include sex, age group and race.
MEDICAL HISTORY
A subject data listing of medical and surgical history will be provided.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded using the World 
Health Organization Drug Dictionary (WHO DD) (March 2024).  Prior medications will 
be defined as medications that stopped before the 1st dose of study drug.  Concomitant 








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ECG results.  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
The total number of doses administered at each dose level will be summarized for each 
subject. This table will also present the number of missed or delayed doses. In addition, a 
table showing the duration of drug exposure at each dose will be generated for each 
subject.
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities
(MedDRA).  Adverse events will be coded to the MedDRA (Version 27) lower level term 
(LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged during 
treatment, 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 
is continuous.
During treatment is defined as the period between the administration of study drug and up 
to 113 days after the last study drug dose.  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 dose.  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 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 treatment-related TEAEs will be summarized 
by SOC and PT.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study treatment.  
Adverse events will be summarized on the Safety Analysis Set.  The number of adverse 
events, number of subjects with adverse events, and incidence (%) will be calculated by 
dose and overall.  To obtain the incidence (%), the number of subjects with at least 1 
event and the percentage of subjects with adverse events by system organ class (SOC) 
and by preferred term (PT) in the Safety Analysis Set will be calculated.  
Separate listings will be provided for subjects with deaths, SAEs, and AEs leading to 
discontinuation.


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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 postbaseline visit and to the end of treatment will be summarized by visit 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 nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be graded or 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.  Each laboratory parameter will be assessed based on shift 
tables that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit and at the end of treatment.
Appendix 13.2 presents the criteria (based upon Common Terminology Criteria for 
Adverse events (CTCAE) Version 5.0) 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 is defined as a postbaseline value with 
an increase from baseline to a grade of 3 or higher. A listing of subjects with markedly 
abnormal laboratory values will be generated, which will be ordered by subject.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, body temperature, weight) and changes from baseline will be presented by 
visit. 
Vital sign parameter values will also be presented in a listing, ordered by subject.
5.6.5
Electrocardiograms
Shift tables will present changes from baseline in ECG interpretation (categorized as 
normal; abnormal, not clinically significant; and abnormal, clinically significant) by visit 
to end of treatment.
5.6.6
Other Safety Analyses
A listing presenting Columbia-Suicide Severity Rating Scale (C-SSRS) assessment results
for all subjects will be generated which will be ordered by subject.
5.7
Other Analyses
The presence of anti-E2814 antibodies at various time points postdose will be presented 
in subject data listings.  The number (percentage) of subjects with positive and negative 
anti-drug antibody (ADA) in serum and plasma will be summarized by visit and dose.  A 
summary table showing ADA subject level status will be presented by dose, together with 




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
Zero for time points prior to the first non-zero concentration following single (or 
first) dosing in a linear plot

“Missing” for time points after the first non-zero concentration following single 
(or first) dosing in a linear plot

“Missing” for all BLQ values in a semi-logarithmic plot
When calculating the mean (or median) value for the concentration at a given time point, 
all BLQ values are assigned as zero.  If the proportion of values reported as BLQ is more 
than 50% or the calculated mean (or median) value is less than LLOQ at a time point, the 
value of mean (or median) is treated as:

Zero for time points prior to the first non-zero mean (or median) concentration 
following single (or first) dosing in a linear plot

“Missing” for time points after the first non-zero mean (or median) concentration 
following single (or first) dosing in a linear plot

“Missing” for all BLQ values in a semi-logarithmic plot
8.1.4
Handling of Anomalous Concentration Values
Anomalous values are those that are inconsistent with known or expected PK behavior of 
the drug but are not defined on the basis of statistical tests for outliers.  Individual 
concentrations deemed to be anomalous can be excluded from the PK analysis and median 
and mean profiles.  Anomalous values will be identified in the CSR.  Clear justification 
must be provided in the CSR for exclusion of any data.
8.1.5
General Rules for Presentation of Drug Concentrations and PK
Parameters
When presenting individual/raw (raw, hereafter) values and summary statistics, the 
following rule will be applied: for drug concentrations and concentration-dependent 
pharmacokinetic parameters, all summary statistics (mean, median, geometric mean, SD, 
and CV) will have 3 significant digits.  For tmax and tlag, raw values and median have fixed 
2 decimal places.
Typical variable
Standard 
Unit
(depends on 
compound)
N
Digit rule
Raw
Minimum
Maximum
Mean
Median
SD
Geometric  
Mean
CV
(%)
E2814
concentration
Plasma/serum 
ug/mL
CSF ng/mL
X
Significant digits
3
3
3
-
-
Cmax, Cmin
Plasma/serum 
ug/mL
CSF ng/mL
X
Significant digits
3
3
3
3
3


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Typical variable
Standard 
Unit
(depends on 
compound)
N
Digit rule
Raw
Minimum
Maximum
Mean
Median
SD
Geometric  
Mean
CV
(%)
tmax, tlaga
h
X
Fixed decimal 
places
2
2
-
-
-
λz
1/h
X
Significant digits
3
3
3
3
3
t1/2
h
X
Significant digits
3
3
3
3
3
AUC
Plasma/serum 
ug·h/mL
CSF ng.h/mL
X
Significant digits
3
3
3
3
3
%AUCex
%
X
Significant digits
3
3
3
3
3
CL
L/h
X
Significant digits
3
3
3
3
3
Vd
L
X
Significant digits
3
3
3
3
3
MRT
h
X
Significant digits
3
3
3
3
3
a:  Mean, SD, geometric mean and CV will not be calculated for tmax and tlag.
CV(%) = sqrt(exp[SD2 of log transformed data]-1)×100
8.1.6
General Rules for Presentation of PD Parameters
Summary statistics for the PD data will be presented to 3 significant digits.
For the PD biomarker assays, the LLOQ and ULLQ values will be provided together with 
the data.
When producing TLGs for the PD data, BLQ and ALQ values in tables and figures will 
be handled as follows:
For Free MTBR-Tau species (including, Free MTBR-Tau-299 and Free MTBR-Tau-354)
and other PD biomarkers apart from Bound MTBR-tau species, 
•
BLQ values will be replaced with 0.5 x LLOQ and ALQ values replaced with 2 x 
ULOQ.
For Bound MTBR-tau species (including, Bound MTBR-Tau-299 and Bound MTBR-
Tau-354):
•
A concentration that is BLQ is assigned a value of zero if it is pre-dose or if it occurs 
in a profile after dosing at time zero and before the first measurable concentration.
•
If a BLQ value occurs after a measurable concentration and is followed by a value 
above the lower limit of quantification, then the LLOQ/2 is used.
•
If a BLQ value occurs after the last quantifiable concentration it is treated as LLOQ/2.
For listings no derivations are required therefore values of BLQ and ALQ will be 
presented.
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.


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Final (Version 1.0)
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Page 17 of 22
10 STATISTICAL SOFTWARE
Analysis will be performed using SAS (release 9.4 or newer), Phoenix WinNonlin (version 
6.4 or newer) and Microsoft Excel (2010 or newer).
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
User Manual 302-104.01. Non-compartmental pharmacokinetic analysis. Version Date 
28th June 2018.


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Final (Version 1.0)
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Confidential
Page 18 of 22
13 APPENDICES
13.1
Derivations for Clinical and Cognitive Assessments.
Geriatric Depression Scale: Short Form
1. Are you basically satisfied with your life? YES / NO
2. Have you dropped many of your activities and interests? YES / NO
3. Do you feel that your life is empty? YES / NO 
4. Do you often get bored? YES / NO
5. Are you in good spirits most of the time? YES / NO
6. Are you afraid that something bad is going to happen to you? YES / NO
7. Do you feel happy most of the time? YES / NO
8. Do you often feel helpless? YES / NO
9. Do you prefer to stay at home, rather than going out and doing new things? YES / NO 
10. Do you feel you have more problems with memory than most? YES / NO
11. Do you think it is wonderful to be alive now? YES / NO
12. Do you feel pretty worthless the way you are now? YES / NO
13. Do you feel full of energy? YES / NO
14. Do you feel that your situation is hopeless? YES / NO
15. Do you think that most people are better off than you are? YES / NO
Answers in bold indicate depression. Score 1 point for each bolded answer.
A score > 5 points is suggestive of depression.
A score ≥ 10 points is almost always indicative of depression
For each of the following assessments, (Functional assessment scale [FAS], 
Neuropsychiatric Inventory–Questionnaire [NPI-Q], Memory Assessment Questionnaire 
[MAC-Q]), sum the individual component scores to generate a summary score for each. If 
a response is NA or unknown, treat as missing. If at any given visit, the number of 
missing items within a questionnaire is less than 30% of the total number of items, then 
the score for this component at this visit will be calculated as the sum of the non-missing 
items multiplied by the ratio of the total number of items to the number of the non-
missing items. If the number of missing items is equal to or greater than 30%, then the
score at this visit is considered missing. 
Values captured within the FAS as ‘not applicable (e.g., never did)’ (NA) will be treated 
as missing.
13.2
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 1.


Statistical Analysis Plan
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Page 19 of 22
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
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


Statistical Analysis Plan
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Final (Version 1.0)
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Page 20 of 22
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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
Fibrinogen plasma-low
>125 - 175 mg/dL
>80 – 125 mg/dL
50- 80 mg/dL
<50  mg/dL
Fibrinogen plasma-high
425 - 500 mg/dL
>500 - 600 mg/dL
>600 - 700 mg/dL
> 700 mg/dL
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
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 


Statistical Analysis Plan
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Page 21 of 22
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood 
cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published:  27 Nov 2017.


Statistical Analysis Plan
E2814-G000-103
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Final (Version 1.0)
23 Jul 2024
Confidential
Page 22 of 22
SIGNATURE PAGE
Author:
Primary Statistician 
Eisai Ltd
Date
Approval:
Translational Science Biostatistics
Eisai Inc.
Date
Study Director
 
 
Eisai Inc.
Date
PPD
PPD
PPD
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PPD
PPD