Conditions: Alzheimer Disease Dementia, Alzheimer Type
Keywords: E2609 Mild Cognitive Impairment Mild to Moderate Dementia Alzheimer's Disease Prodromal Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
This is a Phase 2 study to evaluate safety and efficacy in participants with Mild Cognitive Impairment due to Alzheimer's Disease/Prodromal Alzheimer's Disease (referred to as MCI/Prodromal) and mild to moderate dementia due to Alzheimer's Disease (referred to as mild to moderate AD). This study will have a Core Phase and an Extension Phase.

Detailed description:

Arms:
arm 1: A low dose of E2609 will be assessed. arm 2: A middle dose of E2609 will be assessed. arm 3: A high dose of E2609 will be assessed. arm 4: None arm 5: A low dose of E2609 will be assessed. arm 6: A high dose of E2609 will be assessed. arm 7: None arm 8: A middle dose of E2609 will be assessed.

Interventions: intervention 1: E2609 intervention 2: Placebo
Intervention descriptions: intervention 1: Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food. intervention 2: Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.

Protocol document:
Prot_000.pdf: 
Synoptic Clinical Study Report 
E2609-G000-202 
 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the study protocol and all previous versions are provided on the following 
pages: 
• V10.0, 10 Dec 2018 (Amendment 08) 
• V9.0, 01 Feb 2017 (Amendment 07) 
• V8.0, 02 Nov 2016 (Amendment 06) 
• V7.0, 26 Sep 2016 (Amendment 05) 
• V6.0, 29 Jun 2016 (Amendment 04) 
• V5.0, 06 Feb 2016 (Amendment 03) 
• V4.0, 05 Nov 2015 (Amendment 02) 
• V3.0, 28 May 2015 (Amendment 01) 
• V2.0, 21 Oct 2014 (revised original protocol) 
• V1.0, 15 Jul 2014 (original protocol) 
 
Page 1 of 1658
Eisai
Confidential


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page i of xxvi
REVISION HISTORY
Revisions to Version 9.0 
New version/date:  Version 10.0/10 Dec 2018 (per Amendment 08)
Change
Rationale
Affected Protocol 
Sections
Added an additional 24 months 
to the Extension Phase.
To continue to assess the long-term 
safety and tolerability of 
elenbecestat 50 mg per day in 
subjects who elect to continue with 
open-label treatment.
Synopsis 
•
Study Period and 
Phase of 
Development
•
Objectives
•
Study Design
•
Duration of 
Treatment
•
Endpoints
•
Analyses
Section 9.1
Section 9.2.5
Appendix 6
Revised interim safety 
assessments for Years 3 to 4 of 
the Extension Phase to be 
4 months apart.
To reduce subject burden.
Synopsis 
•
Study Design
Section 9.1.3
Appendix 6
Added that if subjects have non-
MRI compatible devices fitted 
during treatment, then a 
computed tomography scan 
may be utilized to assess safety, 
if deemed appropriate by the 
investigator
To clarify that subjects would not 
need to withdraw from study.
Synopsis 
•
Study Design
Section 9.1.3
Section 9.5.1.5.7
Appendix 6 (Extension 
Phase Assessments)
Revised Visits 33 and 34 as 
visits in the treatment period.  
The Follow-up Visits at 4 
weeks and 12 weeks will be 
renamed as Follow-up Week 4 
Visit and Follow-up Week 12 
Visit, respectively.
For clarity purposes.
Synopsis
•
Safety Assessments 
(Extension Phase)
Section 9.5.1.5.1
Section 9.5.4.1
Appendix 6
•
Table 14
Revised Peripheral blood 
mononuclear cells (PBMCs) 
during the Extension Phase to
be collected at baseline 
(Visit 21), 6 months (Visit 26), 
12 months (Visit 28), and 24 
months (Visit 32) only.
Based on new guidance from the 
DSMB.
Synopsis 
•
Safety Assessments
(Extension Phase)
Section 9.2.5
Section 9.5.1.5
Appendix 6 (Extension 
Phase Assessments)
Page 2 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page ii of xxvi
Revisions to Version 9.0 
New version/date:  Version 10.0/10 Dec 2018 (per Amendment 08)
Change
Rationale
Affected Protocol 
Sections
•
Table 13
•
Table 14
During the Extension Phase, 
lymphocyte subsets will be 
assessed during the first 12 
months only.
Based on new guidance from the 
DSMB.
Synopsis 
•
Safety Assessments
(Extension Phase)
Section 9.4.7
Appendix 2
•
Listing 2
Appendix 6
•
Table 13
•
Table 14
Removed requirement for 
treatment discontinuation based 
on amyloid-related imaging 
abnormalities or findings of 
average QTcF >500 msec.
To align with the safety criteria for 
discontinuation in the Phase 3 
program
Appendix 6 (Safety-
related criteria for 
discontinuation of study 
drug)
Added that any amyloid-related 
imaging abnormalities and 
treatment-emergent 
depigmentation/
hypopigmentation/vitiligo/loss 
of hair color will require 
collection of information 
sufficient to provide detailed 
description of the events 
treatment and outcome to the 
Medical Monitor for the study.
To ensure sufficient information is 
collected for full description of 
these events
Section 9.5.1.5
Removed requirement for food 
while taking study drug.
To reduce patient burden as current 
clinical pharmacology data indicate 
that food has minimal 
pharmacodynamic impact.  
Synopsis 
•
Study Treatments
(Extension Phase)
Appendix 6 (Treatments)
Subjects with abnormal urine 
pregnancy test will have a 
serum pregnancy performed.
Correction in instruction
Appendix 6
•
Table 14
Added clarification that the 
clinical assessment of suicidal 
thinking and behavior will be 
conducted only at visits that do 
not include administration of 
the Columbia Suicide Severity 
Rating Scale (C-SSRS) and that 
a positive suicidality assessment 
To clarify when the C-SSRS will be 
administered.
Synopsis 
•
Safety Assessments
(Extension Phase)
•
Safety Analyses
(Extension Phase)
Section 9.2.5
Section 9.5.1.5
Page 3 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page iii of xxvi
Revisions to Version 9.0 
New version/date:  Version 10.0/10 Dec 2018 (per Amendment 08)
Change
Rationale
Affected Protocol 
Sections
from the subject or the 
caregiver/informant on the 
clinical assessment of 
suicidality (ie, a “yes” response 
on the clinical assessment of 
suicidal thinking and behavior) 
would trigger the C-SSRS to be 
administered.
Section 9.5.1.5.11
Appendix 6 (Extension 
Phase Assessments)
•
Table 14
Added instruction that the 
investigator should review and 
determine whether positive 
assessments in suicidal thinking 
and behavior constitute an 
adverse event.
To ensure that any positive 
assessments in suicidal thinking 
will be assessed as potential adverse 
events.
Section 9.5.1.5.1
Revised definition of Extension 
Phase Safety Analysis Set
Clarification
Synopsis
•
Analysis Sets
Appendix 6 (Extension 
Phase Analysis Sets)
An editorial revision was made 
to remove “(E2609)” in the text 
of the protocol
Elenbecestat is now a recommended 
International Nonproprietary Name
(rINN)
Throughout
Editorial changes
Correction
Throughout
Page 4 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page iv of xxvi
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
An editorial revision was made 
to add “elenbecestat”, the 
proposed International 
Nonproprietary Name (pINN) 
for “E2609”; grammatical, 
typographical, and formatting 
changes were also made.
The revision was made to provide 
consistency for current and future 
elenbecestat (E2609) clinical 
development documents.
All sections of the 
protocol that previously 
included “E2609” or 
required editorial revision
A Open-label Extension (OLE) 
Phase of up to 24 months was 
added to the protocol specifying 
that eligible subjects who elect 
to continue open-label treatment 
after completing Visit 20 will 
receive elenbecestat (E2609)
50 mg per day. A detailed 
description of the OLE Phase 
was added in Appendix 6.
An editorial revision was made 
referring to the original “study” 
(Prerandomization and
Randomization Phases) as the 
“Core Study”.
The OLE was added to assess long-
term safety and tolerability of 
elenbecestat (E2609) 50 mg per day 
in subjects who elect to continue 
open-label treatment after Visit 20.  
The editorial revision was made for 
clarity of presentation where 
description of the OLE procedures 
has been added.
Synopsis 
•
Study Period and 
Phase of 
Development
•
Objectives
•
Study Design
•
Inclusion Criteria
•
Exclusion Criteria 
•
Study Treatment 
•
Duration of 
Treatment
•
Concomitant 
Drug/Therapy
•
Assessments
•
Endpoints
•
Analysis Sets
•
Analyses
Section 7
Section 8
Section 9.1
Section 9.2.4.3
Section 9.2.4.4
Section 9.2.5
Section 9.3
Section 9.3.3
Section 9.4.1
Section 9.4.7
Section 9.5.1.2.1
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.1.4.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.4.1
Page 5 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page v of xxvi
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Section 9.5.5
Section 9.7.1
Appendix 6
Addition of the OLE Phase to 
evaluate the long-term safety 
and tolerability of elenbecestat
(E2609) and cross reference to 
the detailed OLE Phase protocol 
in Appendix 6.
To add the OLE Phase in the 
context of the elenbecestat (E2609)
clinical development program and 
study design to provide 
investigators with the location of 
the complete detailed OLE Phase 
protocol.
Section 7
Section 9.1
Section 9.1.3
Addition of cross reference to 
objectives for OLE Phase 
protocol in Appendix 6.
To provide investigators with the 
location of the OLE Phase 
objectives.
Section 8
Safety aspects have been built 
into the study design in light of 
the preclinical and clinical 
safety data with elenbecestat 
(E2609) to mitigate clinical risk 
are extended to the OLE Phase 
and 2 off-treatment Follow-Up 
Visits at 4 and 12 weeks after 
the last dose of study drug 
during the OLE Phase are 
added.
To provide instruction to 
investigators for continued 
monitoring procedures for 
mitigation of potential clinical risk
associated with elenbecestat
(E2609).
Section 9.2.5
Section 9.3.3
Section 9.5.1.5.7
Section 9.5.5
Addition of requirement that 
subjects meet all inclusion 
criteria and not meet any of the 
exclusion criteria for the OLE 
Phase, with cross reference to 
the criteria for the OLE Phase in 
Appendix 6.
To provide investigators with the 
requirements for subject eligibility
and the location of the OLE Phase 
inclusion and exclusion criteria.
Section 9.3
Addition of cross reference to 
criteria for discontinuation of 
study drug during the OLE 
Phase in Appendix 6.
To provide investigators with the 
location of the criteria for 
discontinuation of study drug 
during the OLE Phase.
Section 9.3.3
Prior and concomitant therapy 
restrictions are extended to the 
OLE Phase.
To provide instruction to 
investigators for prior and 
concomitant therapy during the 
OLE Phase.
Section 9.4.7
Addition of cross reference to 
Table 14.
To direct the investigators to the 
detailed OLE Phase Schedule of 
Procedures/Assessments in 
Section 9.5.1.2.1
Section 9.5.1.3.1
Page 6 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page vi of xxvi
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Study 202:  Open-label Extension 
Phase (Visit 21 through Visit 32).
Section 9.5.1.3.2
Section 9.5.1.4.2
Section 9.5.1.5
Section 9.5.1.5.1
Sections 9.5.1.5.3 to 
9.5.1.5.11
Section 9.5.2
Section 9.5.5
Addition of requirement to 
report all adverse events (AEs) 
observed during the OLE Phase; 
clarification that Visit 20 is the 
last visit for subjects who do not 
enter the OLE Phase and that 
Visit 34 is the last study visit 
for subjects who enter the OLE 
Phase.
Added for clarification.
Section 9.5.1.5.1
Removed instructions for SAE 
reporting outside of the 
reporting period.
To match the standard template for 
SAE reporting.
Section 9.5.1.5.1
Addition of ECG Assessments 
during the OLE Phase.
To specify that a single 12-lead 
ECG will be performed during the 
OLE Phase.
Section 9.5.1.5.6
Addition of Dermatologic 
Assessments during the OLE 
Phase.
To stipulate that evaluation of skin 
assessments will be performed by 
the investigator during the OLE 
Phase.
Section 9.5.1.5.8
Page 7 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page vii of xxvi
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Addition of requirement to 
report all serious adverse events 
(SAEs) observed during the 
OLE Phase; clarification that 
Visit 20 is the last visit for 
subjects who do not enter the 
OLE Phase and that Visit 34 is 
the last study visit for subjects 
who enter the OLE Phase.
Added for clarification.
Section 9.5.4.1
Addition of cross reference to 
Appendix 6 for discussion of 
OLE Phase statistical analyses.
To provide investigators the 
location of the OLE Phase 
statistical analyses discussion.
Section 9.7.1
The term “total lymphocyte
count” was changed to
“absolute lymphocyte
count”.
To ensure consistency throughout 
the protocol and consistency with 
reports generated by the central 
laboratory.
Synopsis 
•
Concomitant 
Drug/Therapy
Section 9.2.5
Section 9.4.7
Section 9.5.1.5.3
Table 7
Appendix 2
Page 8 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page viii of xxvi
Revisions to Version 7.0
New version/date:  Version 8.0/02 Nov 2016 (per Amendment 06)
Change
Rationale
Affected Protocol 
Sections
Subjects currently receiving 5 
or 15 mg elenbecestat (E2609)
will be re-assigned to 50 mg 
elenbecestat (E2609) for the 
remainder of the double-blind 
treatment period provided they 
will receive at least 12 weeks of 
double-blind treatment after the 
re-assignment, (ie, no dose 
reassignments past Visit 17).
As elenbecestat (E2609) 50 mg has 
been selected as the appropriate 
dose for Phase 3 development, 
subjects should not continue with 
doses that are not being advanced 
clinically. Additionally, the 
re-assignment of subjects in
elenbecestat (E2609) 5 and 15 mg 
to elenbecestat (E2609) 50 mg will 
further the safety and tolerability 
data in subjects exposed to 
elenbecestat (E2609) 50 mg.
Synopsis 
•
Study Design
•
Number of Subjects
•
Sample Size 
Rationale
Section 7.1
Section 9.1
Section 9.1.2.1
Section 9.4.1
Section 9.4.4
Section 9.5.2
Clarified that one of the 
exploratory endpoints will 
analyze change from baseline in 
CSF amyloid and CSF BACE1 
measurements from 4 weeks 
and up to 18 months of 
treatment only.  There will no 
analysis for treatment follow-
up.
Correction
Synopsis 
•
Analysis for 
Exploratory 
Endpoints
•
Exploratory 
Objective
Section 8.3
Section 9.7.1.1.3
Section 9.7.1.6.3
The frequency of DSMB safety 
reviews after the 12-week 
interim safety analysis will be 
reassessed and details will be 
provided in the DSMB charter.
The DSMB charter will provide full 
details of interim safety reviews.
Synopsis 

Study Design
Section 9.1
Removed the statement that 
subjects must be stable on 
acetylcholinesterase inhibitor
(AChEI) or memantine to be 
included in the primary 
analyses.
This statement is no longer relevant 
as of Amendment 05.
Synopsis 
•
Concomitant 
Drug/Therapy
Section 9.4.7
Added a statement to specify 
that additional analyses will be 
performed for subjects with
dose re-assignment and details 
of these analyses and treatment 
group definitions will be 
provided in the statistical 
analysis plan (SAP); clarified 
that the SAP will be finalized 
before database lock.
To clarify that the SAP will be 
finalized prior to database lock and 
it will provide full details of the 
analyses to be performed for this 
study. 
Section 9.7.1
Page 9 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page ix of xxvi
Revisions to Version 6.0
New version/date:  Version 7.0/26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Removed Stage B from protocol. In 
line with this decision, the study 
objectives and endpoints have been 
modified and subjects who 
discontinue study drug early for any 
reason will no longer be required to 
complete efficacy visits after last 
dose of study drug.
This study will no longer 
be a Proof-of-Concept 
study.  
Synopsis 
•
Study Protocol Title
•
Investigators
•
Sites
•
Study Period and Phase 
of Development
•
Objectives
•
Study Design
•
Early Discontinuation
•
Number of Subjects
•
Study Treatments
•
Efficacy Assessments
•
Safety Assessments
•
Statistical Methods
•
Study Endpoints
•
Analysis Sets
•
Efficacy and Biomarker 
Analyses
•
Analysis for the 
Primary/Secondary/Explo
ratory Endpoints
•
Pharmacokinetic 
Analyses
•
Pharmacokinetic 
/Pharmacodynamic 
Analyses
•
Interim Analyses
•
Sample Size Rationale
Section 6
Section 7
Section 8
Section 8.3
Section 9.1
Section 9.2.1
Section 9.2.3
Section 9.2.4.4
Section 9.2.5
Section 9.3
Section 9.4.3
Page 10 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page x of xxvi
Revisions to Version 6.0
New version/date:  Version 7.0/26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Section 9.4.4
Section 9.4.7
Section 9.2.5
Section 9.5.1.3.1
Section 9.5.1.4.2
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.4.1
Section 9.5.5
Section 9.7
Section 10
Updated Eisai contact information 
Change in personnel and 
move to Building 100
•
Title Page
•
Protocol Signature Page
Page 11 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xi of xxvi
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of investigational 
sites (from 40 to 35)
Feasibility

Synopsis -
•
Study Design
•
Sites
Section 6
Section 9.1
Section 9.3
Removed Exclusion Criterion No. 
44 for male subjects regarding 
restrictions on child bearing  
No longer a safety concern;
E2609 has not shown a 
deleterious effect on sperm in 
preclinical reproductive toxicity 
studies.

Synopsis:
•
Exclusion Criteria
Section 9.3.2
Added option for subjects who 
provided a CSF sample prior to 
randomization but who declined the 
CSF sample collection after 4 weeks 
of dosing to provide a postdose CSF 
sample at any point in the study (ie, 
even after 4 weeks of dosing).
Reflects the added value of CSF 
data for the PK/PD secondary 
objective of this study.  In 
addition, given that PK steady 
state is achieved within the 1st 
2 weeks of initiation of dosing, 
data collected post Week 4 visit 
is still considered to be 
applicable in assessment of the 
steady state effect.

Synopsis -
•
Pharmacodynamic
Assessments
Section 5.3
Section 9.1
Section 9.1.1.2
Section 9.5.1.3.3
Section 9.5.1.4
Table 6
Table 7
Table 8
Revised details of restrictions to 
anticoagulant therapy and short-
term steroid use revised/moved 
details regarding antiplatelet drugs 
to the main body of the protocol
To assist in subject recruitment 
and retention and considering 
that the strict restrictions were 
not necessary for subject safety

Synopsis -
•
Concomitant 
Drug/Therapy
Section 9.4.7
Appendix 2
Removed the 33% decrease from 
baseline for CD4, CD8, and CD19 
as a trigger for more frequent 
testing of flow cytometry and 
CBCs. Additional safety 
monitoring for CD4, CD8, CD19, 
and CBCs will only be based on the 
population adjusted LLNs for 
clinically asymptomatic subjects. 
Experience to date has indicated 
significant variability within the 
normal range, both for increases 
and decreases. Absolute counts 
of lymphocyte subsets are more 
meaningful than percentage 
decreases for triggering more 
frequent monitoring.
Section 9.3.3
Table 1
Table 2
Page 12 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xii of xxvi
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Added option to temporarily 
suspend study drug for subjects who 
are clinically asymptomatic but who 
meet CD4, CD8, or CD19 
discontinuation thresholds on 
2 consecutive tests.  Introduce rules 
for ability to re-start study drug (ie, 
rechallenge) in these subjects.   
Only 1 cycle of temporary 
suspension and rechallenge with 
study drug permitted for any 
individual subject.  
To assist in subject retention and 
to gain knowledge on the 
behavior of lymphocyte subsets 
on rechallenge.
Section 9.3.3
Table 1
Table 2
Added extra blood draw times with 
focus on lymphocyte subsets, 
CBCs, and immunoglobulins during 
the 12-week safety follow-up for all 
subjects.
To increase frequency of key 
safety monitoring parameters in 
post-treatment follow-up period 
so as to assess immunological 
changes after completion of 
study drug

Synopsis
•
Study Design
•
Safety Assessments
Section 9.1.2.2
Section 9.1.2.3
Section 9.2.5
Section 9.3.3
Table 7
Table 8
Section 9.5.1.5.7
Section 9.5.5
Clarified that the Functional 
Assessment Questionnaire is to be 
administered to the 
informant/caregiver, and not the 
subject.
Clarification

Synopsis
•
Efficacy 
Assessments
Section 9.5.1.3.1
Added clarification that the Brief 
Smell Identification Test will be 
administered as part of the 
neurological examination
Clarification

Synopsis
•
Safety Assessments
•
Interim Analyses
Section 9.1.1.2
Section 9.5.1.2.1
Section 9.5.1.5.9
Table 6
Table 7
Page 13 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xiii of xxvi
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of randomized 
subjects in Stage A to n=60±20%
To allow for additional 
randomization based upon 
current number of subjects in 
screening at the time of 
amendment implementation

Synopsis
•
Study Design
•
No. of Subjects
Section 7
Section 9.1
Section 9.2.1
Section 9.2.5
Section 9.3
Section 9.7.3
Grammatical, typographical, and 
formatting corrections
Consistency
various
Page 14 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xiv of xxvi
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder of 
the study and the full 
elenbecestat (E2609)
clinical development 
program

Synopsis –
•
Exploratory Endpoint 
Analysis
•
Interim Analysis
Section 9.1
Section 9.1.1.2
Section 9.4.6
Section 9.7.1.7.1
Page 15 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xv of xxvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
•
Secondary Objectives
•
Exploratory Objectives
•
Study Design
•
Exclusion Criterion No. 12
•
Pharmacokinetic 
Assessments
•
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
•
Safety Assessments
•
Secondary Endpoints
•
Exploratory Endpoints
•
Analysis for the Secondary 
Endpoints
•
Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.5
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Appendix 2, Listing 2
Page 16 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xvi of xxvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.

Synopsis –
•
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
•
Inclusion/Exclusion
•
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.4.3

Section 9.3.1

Section 9.5.2

Table 6

Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
•
Inclusion/Exclusion

Section 9.3.2

Section 9.5.2

Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
•
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
Added to provide clarity 

Synopsis –
Page 17 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xvii of xxvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
for the sites.
•
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis –
•
Sites

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1

Figure 2

Section 9.5.1.3.1

Section 9.5.2

Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
•
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3

Table 1

Section 9.5.2

Table 6

Table 7
Page 18 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xviii of xxvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Added 30-day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
•
Study Design
•
Duration of Treatment

Section 9.1

Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2

Table 6
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2

Table 6

Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
•
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3

Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2

Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2

Table 6

Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 19 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xix of xxvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include 
moderate AD subjects
To collect safety data in a 
wider range of AD patients.

Title Page

Synopsis –
•
Objectives
•
Study Design
•
Number of Subjects
•
Inclusion/Exclusion Criteria
•
Study Treatments
•
Efficacy Assessments
•
Study Endpoints
•
Efficacy Analyses
•
Interim Analyses
•
Adaptive Randomization 
•
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1

Section 9.1.1

Figure 1

Section 9.2.1

Section 9.2.2

Section 9.2.3

Section 9.2.4.3

Section 9.2.4.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.4.3

Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2

Section 9.7.1.1.3

Section 9.7.1.4

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.3

Section 9.7.4
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 

Synopsis –
•
Inclusion/Exclusion Criteria

Section 9.3.1
Page 20 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xx of xxvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
cohort.
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for 
the most impaired subject that 
would be eligible for the 
study.  Revising the FAQ 
inclusion from ≤20 to ≤24 is 
consistent with expanding the 
Mild AD cohort to a Mild to 
Moderate AD cohort, and is 
consistent with an MMSE 
inclusion of ≥16.

Synopsis –
•
Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 
cm in diameter) are generally 
not considered clinically 
significant and if discovered 
incidentally no long term 
follow up is routinely 
required.

Synopsis –
•
Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for 
Ig (IgG, IgA, or IgM) to 
specify that levels below the 
LLN at Screening or Baseline
need not be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis –
•
Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for 
subjects who the Investigator 
considers not to have the 
capacity to consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects,
it was necessary to provide 
directions regarding the 
consenting process for 
subjects considered to be 
lacking the capacity to consent 
themselves.

Section 5.3
Revised number of clinical 
sites to 30 from 25
For feasibility purposes.

Synopsis –
•
Sites

Section 6

Section 9.1

Section 9.3
Page 21 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxi of xxvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Added allowance for Tier 1 
and Tier 2 screening 
assessments to be performed
on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the 
same day as the cognitive 
testing for that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis –
•
Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly 
before or shortly after the LP
on CSF days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide 
CSF samples.

Appendix 2; Listing 2
Revised grammar, spelling, 
etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 22 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxii of xxvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis –
•
Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis –
•
Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis –
•
Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
•
Inclusion/Exclusion  
Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and  
International Normalized Ratio 
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
•
Inclusion/Exclusion 
Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –
•
Study Design  

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1
Page 23 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxiii of xxvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
of efficacy assessments.

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol.  The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20 
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis –
•
Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis –
•
Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis –
•
Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline, 
during treatment, and post-
treatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis –
•
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF 
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis –
•
Assessments

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis –
•
Concomitant 
Drug/Therapy

Section 7.1
Page 24 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxiv of xxvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors

Section 9.4.7

Appendix 2, Listing 6
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis –
•
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis –
•
Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis –
•
Analysis of Primary 
Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis –
•
Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Synopsis –
•
Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 
abuse potential.  No longer use the 

Synopsis –
•
Safety Assessments

Section 9.2.5

Section 9.5.1.5.1
Page 25 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxv of xxvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis –
•
Study Endpoints

Section 9.7.1.2
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.5

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Page 26 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page xxvi of xxvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 27 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 1 of 164
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-
Finding Study To Evaluate the Safety and Tolerability of Elenbecestat 
(E2609) in Subjects With Mild Cognitive Impairment Due to Alzheimer’s 
Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia 
Due to Alzheimer’s Disease (revised per Amendments 01 and 05)
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
Elenbecestat (E2609)
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
V6.0
29 Jun 2016 (Amendment 04)
V7.0
26 Sep 2016 (Amendment 05)
V8.0
02 Nov 2016 (Amendment 06)
V9.0
01 Feb 2017 (Amendment 07)
V10.0
10 Dec 2018 (Amendment 08)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local GCP and 
regulations.  All required study documentation will be archived as 
required by regulatory authorities.
Page 28 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 2 of 164
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.
Page 29 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 3 of 164
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-Finding Study To Evaluate 
the Safety and Tolerability of Elenbecestat (E2609) in Subjects With Mild Cognitive Impairment Due 
to Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigators
Investigators in the United States only (revised per Amendment 05)
Sites
Approximately 35 sites, United States only (revised per Amendments 01, 02, 04, and 05)
Study Period and Phase of Development (revised per Amendment 07)
This Phase 2 study will include the following:
Core Study: approximately 32 months including the Prerandomization and Randomization 
Phases (revised per Amendments 05 and 07)
Open-label Extension (OLE) Phase: approximately 51 months including 48 months of 
Treatment Period and 3 months of
off-treatment
Follow-up Period (revised per 
Amendments 07 and 08)
Objectives
Core Study (revised per Amendment 07)
Primary Objective (revised per Amendment 05)
To assess the safety (including immunological and hematological parameters) and tolerability of daily 
dosing with elenbecestat in Mild Cognitive Impairment (MCI)/Prodromal subjects and in subjects 
with Mild to Moderate Dementia due to Alzheimer's Disease (referred to as mild to moderate AD 
throughout the protocol) (revised per Amendments 01 and 07)
Secondary Objectives (revised per Amendments 02 and 05)

To characterize the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of 
elenbecestat 

To assess the effects of elenbecestat on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and up to
18 months of treatment 
Exploratory Objectives (revised per Amendments 01, 02, 04, and 05)

To explore the effects of elenbecestat on CSF Aβ(1-40) and beta (β)-amyloid converting 
enzyme 1 (BACE1) measurements from 4 weeks and up to 18 months of treatment

To explore the effects of elenbecestat compared with placebo on various biomarkers.  
Page 30 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 4 of 164
Biomarkers to be explored may include but are not limited to:
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of elenbecestat compared with placebo on clinical status at various 
time points during 18 months of treatment, and during posttreatment follow-up, by 
assessment of: 
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of elenbecestat on measured clinical 
efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF amyloid isoforms, 
brain amyloid, and vMRI 

To explore relationships between both elenbecestat
dose and exposure, with 
pharmacodynamic (PD) and safety endpoints 
Open-Label Extension Phase (revised per Amendments 07 and 08)
Primary Objective:

To assess the long-term safety and tolerability of daily dosing with elenbecestat 50 mg in 
MCI/Prodromal subjects and in subjects with Mild to Moderate Dementia due to AD
Secondary Objectives

To explore the long-term effects of elenbecestat on clinical status by assessment of: 
a.
The MMSE
b.
The FAQ 

To explore the long-term effects of elenbecestat on:
a.
vMRI including, but not limited to, total hippocampal volume, left and right 
hippocampal volume, whole brain volume, and total ventricular volume with up to 24
and 48 months of treatment in the Extension Phase.
b.
Plasma amyloid at 12, 24, 36, and 48 months of treatment in the Extension Phase.
Study Design
This will be a multicenter, placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
Page 31 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 5 of 164
study with an open-label Extension Phase of up to 51 months in subjects with MCI/Prodromal AD or 
mild to moderate AD.  (revised per Amendment 07)  A common set of inclusion criteria, consistent 
with the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical research criteria for 
MCI due to Alzheimer’s disease (AD) or mild to moderate AD, will be required for all subjects.  In 
addition, the MCI due to AD population will also be consistent with the research criterion for 
“Prodromal AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with the criteria for both MCI due to AD and Prodromal 
AD they will be identified as MCI/Prodromal subjects in this protocol.  The diagnosis of 
MCI/Prodromal AD or mild to moderate AD will be based on both clinical and biological (ie, 
confirmation of amyloid load in the brain) criteria.  (revised per Amendment 01)
The study consists of 3 phases:  Prerandomization, Randomization, and open–label Extension Phase.  
The Prerandomization and Randomization Phases are referred to as the Core Study throughout the 
protocol. (revised per Amendment 07)
Core Study 
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if required 
[revised per Amendment 02]) includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All 
screening assessments (within 4 distinct tiers) must be completed, and eligibility to continue in the 
study confirmed, before any baseline assessments commence.  Following successful completion of 
the Prerandomization Phase, eligible subjects will be randomized and will enter the Randomization 
Phase, which will consist of 2 periods:  Treatment (78 weeks) and Follow-up (post last dose; 
12 weeks).
The study will be limited to approximately 35 sites in the United States.  (revised per Amendments 
01, 02, and 04)  Subjects will initially be randomized 1:1:1:1 to 4 treatment groups (5, 15, or 50 mg 
elenbecestat [E2609] or placebo) within each of the 2 clinical populations.  (revised per Amendments
01, 04, 05, and 06) In addition to the placebo group, 3 elenbecestat doses will be used to reduce CSF 
amyloid β levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, 
respectively, at steady state. PK/PD modeling has shown that these doses should achieve these 
targets when administered once daily (QD) with food, and these doses will be evaluated based on the 
4-week (or later) assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement.  (revised per Amendment 02)  Upon implementation of Amendment 06, at the next 
regularly scheduled visit, subjects receiving elenbecestat 5 or 15 mg who have not yet completed 
Visit 17 (Week 66), will be re-assigned in a blinded manner to elenbecestat 50 mg for the remainder 
of the double-blind Treatment Period. In order to maintain the blind, all subjects who have not yet 
had Visit 17 will go through the same procedures with the placebo-randomized subjects continuing to 
receive placebo and those randomized to elenbecestat 50 mg continuing to receive 50 mg. (revised 
per Amendment 06)
Safety data will be monitored in a blinded fashion on a regular basis.  In addition, approximately 
every 3 months from the time the 1st subject is randomized into the study through the time the last 
subject is randomized, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  (revised per Amendment 06) 
The DSMB will make recommendations to Eisai after each review as to whether any change(s) to the 
study are necessary.  (revised per Amendments 01, 04, and 05)
Interim analyses of the elenbecestat plasma PK for all subjects and the elenbecestat CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of treatment.  
(revised per Amendment 05)  These interim analyses, as well as analyses of safety data, will be 
performed on an ongoing basis throughout the study.  Refer to the Interim Analysis section for more 
detail. These data will be used to evaluate the CSF PD effects of elenbecestat doses, where PD is 
Page 32 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 6 of 164
measured as reductions from baseline in CSF Aβ(1-x) levels.  (revised per Amendments 01 and 02)  
The median and mean percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks or 
more of treatment for each dose of elenbecestat and the 90% CI for the median will be derived. In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data and will relate the average steady state plasma concentration of 
elenbecestat to CSF Aβ(1-x) percentage reduction from baseline determined after at least 4 weeks of 
dosing. (revised per Amendments 01, 02, 03, 04, and 05) 
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug early) an 
interim safety analysis will be conducted by Eisai and the DSMB. At the completion of this interim 
safety review, the frequency of subsequent unblinded safety reviews will be re-evaluated by the 
DSMB and the sponsor and this information will be provided in the DSMB charter. (revised per 
Amendment 06) Subjects will continue study drug while the DSMB reviews all the available safety 
data. (revised per Amendments 01, 04, 05, and 06).
Open-Label Extension Phase (revised per Amendments 07 and 08)
The Extension Phase allows eligible subjects to receive elenbecestat 50 mg daily for up to 48 months 
(4 years).
All subjects who complete 18 months of treatment and 12 weeks of follow-up in the Core Study and 
who satisfy the entry criteria for the Extension Phase are eligible to enter the Extension Phase. After 
completing all Visit 20 procedures in the Core Study Follow-Up Period, eligible subjects will have 
the option to participate in the Extension Phase within 4 weeks of Visit 20 of the Core Study.  These 
subjects may transition to the Extension Phase immediately following Visit 20 (on the same day) if 
the decision to proceed with the Extension Phase has been made at that time.  The medical monitor
must be contacted if Visit 21 is to occur more than 4 weeks after Visit 20.
For all subjects, assessments performed at Visit 20 may serve as Visit 21 (start of the Extension 
Phase) results with the following exceptions: laboratory assessments and vital signs must be repeated 
if Visit 21 occurs more than 10 days from Visit 20.
Subjects who are eligible and who consent to participate in the Extension Phase will be administered 
elenbecestat 50 mg daily at Visit 21.  Subjects with pending INR and serum pregnancy test results 
(females subjects of child bearing potential only) but who are otherwise eligible may begin Extension 
Phase dosing at Visit 21; however, these subjects must discontinue study drug treatment immediately 
if either test result meet the exclusion criteria.
During the Extension Phase, safety assessments will continue to be monitored and all AEs and SAEs 
will be recorded.  Vital signs, hematology, blood chemistry, and urine values will be monitored at 
every scheduled visit.  Clinical assessments (MMSE and FAQ) will be administered every 3 months
for the first 24 months and every 4 months thereafter.  Blood for PD analyses will be collected every
12 months.
All subjects will be assessed using safety MRIs and vMRI measurements at 24 and 
48 months.  Subjects who discontinue early from the Extension Phase will have safety brain MRI and 
vMRI assessments at the Early Discontinuation (ED) Visit if these assessments have not already been 
performed during the preceding 90 days.  If subjects have non-MRI compatible devices fitted during 
treatment, then a computed tomography scan may be utilized to assess safety, if deemed appropriate 
by the investigator. (revised per Amendment 08)
Page 33 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 7 of 164
Early Discontinuation (Core Study)
Subjects who prematurely discontinue taking study drug prematurely for any reason during the Core 
Study will undergo an ED Visit within 7 days of their last dose of study drug.  Follow-up Visits will 
also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug. (revised per Amendments
04 and 05)  
Follow-Up (Core Study)
All subjects, regardless of whether they complete all 18 months of treatment or prematurely
discontinue study drug, will complete 4 post-treatment Follow-up Visits: 2, 4, 8, and 12 weeks after 
the last dose of study drug.  If clinically indicated, more frequent safety assessments can be 
conducted as part of unscheduled (UNS) Visits during the post-treatment Follow-up Period. (revised 
per Amendment 04)
Early Discontinuation (Open-Label Extension Phase) (revised per Amendment 07)
Subjects who prematurely discontinue study drug for any reason during the Extension Phase will 
undergo an ED Visit within 7 days of their last dose of study drug.  Follow-up Visits will also be 
scheduled 4 and 12 weeks after the last dose of study drug.  
Follow-Up (Extension Phase) (revised per Amendments 07 and 08)
All subjects, regardless of whether they complete all 48 months of treatment in the Extension Phase 
or prematurely discontinue study drug, will complete 2 posttreatment Follow-up Visits at 4 and 
12 weeks after the last dose of study drug. (revised per Amendment 07)  If clinically indicated, more 
frequent safety assessments can be conducted as part of UNS visits during the Extension Phase 
Follow-up Period.  
Number of Subjects
Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be screened to provide 
approximately 60 (±20%) randomized subjects (with a target of approximately 15 subjects per 
treatment arm).  There will be no limit to the number of subjects randomized from either clinical 
cohort. (revised per Amendments 01, 02, 04, and 05)
Inclusion Criteria
Core Study
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01) 
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, caregiver or informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on the 
ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted norms in 
delayed recall on the ISLT plus impairment of at least 1 SD from age-adjusted norms in at 
least 1 other computerized learning and memory test (ISLT immediate recall, or 1 of the 
learning and memory components of the CBB). (revised per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
Page 34 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 8 of 164
d.
MMSE ≥16 (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Extension Phase  (revised per Amendment 07)
1.
Subjects who complete the 18-month treatment and the 12-week Follow-up Period (Visit 20) in 
the Core Study and whose Visit 20 falls within a 4-week window from the start of the Extension 
Phase (Visit 21).  Permission must be obtained from the medical monitor if Visit 21 is to occur 
more than 4 weeks from Visit 20.
2.
Subjects must continue to have an identified caregiver or informant who is willing and able to 
provide follow-up information on the subject throughout the course of the Extension Phase.  
Exclusion Criteria (revised per Amendment 04)
Core Study
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
Page 35 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 9 of 164
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory,
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and <1 cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures (revised per Amendments 01 
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<lower limit of normal [LLN]) levels for the testing 
laboratory (if subject is taking vitamin B12 injections, level should be at or above the lower limit 
of normal (LLN) for the testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal malformation 
on physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
Page 36 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 10 of 164
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with: 
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled 
steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL 
respectively.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the investigator 
and the medical monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the medical monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings.  (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate ECGs.  A history of risk factors for 
torsade de pointes (eg, heart failure, hypokalemia, family history of long QT Syndrome) or the 
use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
Page 37 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 11 of 164
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.  Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the 1st dose of study drug.
43. Females of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
Page 38 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 12 of 164
partner with confirmed azoospermia) throughout the entire study treatment period and for 
28 days after study drug discontinuation.
b.
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 days 
after study drug discontinuation.
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the 
same contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Extension Phase (revised per Amendment 07)
1.
Subjects who discontinue study drug prematurely during the Core Study are not eligible to 
participate in the Extension Phase.
2.
Subjects with any active infection within 4 weeks of Visit 21. 
3.
Subjects with absolute lymphocyte count below the LLN within 10 days of Visit 21.
4.
Subjects who develop the following conditions from the time of screening for the Core Study to
the start of the Extension Phase: 
a.
Hepatic impairment, with total bilirubin greater than 1.5×ULN or INR greater than 1.7.  
Subjects with Gilbert’s syndrome need not be excluded on the basis of an elevated 
bilirubin, provided that they have no other signs or symptoms suggestive of hepatic 
impairment
b.
Any contraindications to MRI scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as 
safe for use in MRI scanners)
c.
Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
d.
Immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
e.
Chronic viral hepatitis
f.
TB
g.
Ophthalmic shingles
h.
Ocular HSV infection
i.
Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  

Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled 
by inhaled steroids need not be excluded

Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and 
not on systemic immunosuppressive therapy need not be excluded
Page 39 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 13 of 164

Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted)
j.
Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the skin, or 
localized prostate cancer that did not require systemic therapy; these do not exclude the 
subject from the Extension Phase).
5.
Subjects with prolonged QTcF interval at Visit 20 or Visit 21. Subjects with a single 12-lead 
ECG QTcF >450 msec should have 2 additional ECGs performed at least 1 min apart and the 
mean QTcF from the triplicate ECGs should be calculated. Subjects with a mean QTcF value 
>450 msec are not eligible to enter the Extension Phase.
6.
Subjects with significant pathological findings on brain MRI including but not limited to: an area 
of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, 
encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple 
lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white 
matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as 
meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be 
exclusionary).
7.
Subjects who have a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5 at Visit 20 or 
Visit 21 or any suicidal behavior during the study before the start of the Extension Phase.
8.
Female subjects of child bearing potential who meet any of the follow criteria:
a.
Do not agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period and for 
28 days after study drug discontinuation
b.
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 days 
after study drug discontinuation
c.
Who do not agree to use the same contraceptive during the study treatment period or for 
28 days after study drug discontinuation.
9.
Females who are lactating or pregnant (as documented by a positive β-hCG or hCG test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Visit 20 or Visit 21.  
10. Subjects with medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are 
not stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments.
11. Any other clinically significant abnormal findings in vital signs, ECGs, and laboratory tests that 
would, in the investigator’s opinion, would affect the subject’s safety or interfere with study 
assessments during the Extension Phase.
Study Treatments (Core Study)
Elenbecestat (E2609) tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets to 
match elenbecestat will be of identical appearance. Each subject will receive 2 tablets, which when 
combined will make up the required doses of elenbecestat or placebo, to be administered orally QD 
with food. (revised per Amendment 05)
Study Treatments (Extension Phase) (revised per Amendments 07 and 08)
Page 40 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 14 of 164
Elenbecestat tablets of 50-mg dose strengths will be supplied during the Extension Phase. Each 
subject will take 1 tablet orally QD, with or without food.
Duration of Treatment
Core Study
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising the following: 

Screening and Baseline Periods (Prerandomization Phase): up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, the 
duration of the pre-randomization phase can be extended by up to 4 weeks to allow additional 
time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-up Period (Randomization Phase): 12 weeks (post last dose)
Extension Phase (revised per Amendments 07 and 08)
The duration of the Extension Phase will be approximately 220 weeks, comprising the following:

Treatment Period:  up to 208 weeks (48 months)

Follow-up Period:  12 weeks (after the last dose)
Concomitant Drug/Therapy (Core Study and Extension Phase)  (revised per Amendments 04 and 
07)
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit in the Core Study (for subjects 
participating in the Core Study only) or the last treatment visit in the Extension Phase (for subjects 
participating in the Extension Phase)  (see Appendix 2 for a detailed listing of these agents) (revised 
per Amendment 07):
Drugs that may cause QTc prolongation are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization.
Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days (whichever is 
longer) before randomization.
Live vaccines are not permitted within 3 months before randomization.  This does not apply to 
non-live/inactivated vaccines.
Ig therapy and biologic drugs are not permitted within 6 months before randomization.
Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization.  However, during 
the Treatment Period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the medical monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started.  Complete 
blood count and lymphocyte subsets (for Core Study and first 12 months of Extension Phase 
only) should be determined before starting steroid treatment and continue to be monitored 
weekly. (revised per Amendment 08) Study drug may be resumed after discussion with the 
medical monitor when the following conditions are met: (1) treatment with steroids has been 
completed for at least 1 week; (2) absolute lymphocytes not <LLN; (3) no lymphocyte subsets 
are below the discontinuation threshold (for Core Study only); (4) the investigator considers that 
Page 41 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 15 of 164
the medical condition which required treatment with steroids has improved or resolved.  Weekly 
testing of lymphocyte subset counts (for Core Study only) and CBC with differentials (for Core 
Study and Extension Phase) is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
(revised per Amendments 06 and 08)
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for any efficacy analyses.  
(revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  
Must be on stable dose for at least 4 weeks before randomization, except for medications that are 
administered as short courses of treatment or which are to be used intermittently as needed.  
Subjects who are on anticoagulants may have a variable dose but should have stable 
anticoagulation control for at least 4 weeks before randomization.  They may be required to stop 
their anticoagulant medication prior to CSF collection and then restart this medication after the 
LP procedure, as per local guidelines.  (revised per Amendment 04)
Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a period 
of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator, 
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks
Antiplatelet therapy: (revised per Amendment 04)
For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any other 
antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and clopidogrel (or 
any other antiplatelet drug which is not aspirin) in combination are also permitted but subjects 
who are on such a combination of antiplatelet drugs may be required to stop 1 or more of these 
antiplatelet drugs before the LP procedure and restart after the LP as per local guidelines.
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, individually 
or in combination, are permitted. 
Assessments
Efficacy Assessments (Core Study)
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.
Mini-Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing. 
International Shopping List Task:  The ISLT is a verbal learning and episodic memory test assessing 
Page 42 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 16 of 164
both immediate and delayed recall.  
CogState Brief Battery:  A computer-based battery comprising 4 cognitive tests: 

Detection – a simple reaction time test.  Speed of response is the measure.

Identification – a simple choice reaction time test.  Speed of response is the measure.

One Card Back – a simple working memory test.  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
Functional Assessment Questionnaire:  The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.   The caregiver or informant provides performance ratings on 
10 complex activities of daily living performed within the preceding 4 weeks.  (revised per 
Amendment 04)  
Volumetric Magnetic Resonance Imaging:  vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments (Core Study)
Blood samples will be collected for the determination of the concentrations of elenbecestat.
For 
subjects who consent to CSF sample collection, CSF samples will be collected for the determination 
of elenbecestat concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations 
may be performed depending on emerging data from other studies with elenbecestat.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments (Core Study)
Brain atrophy will be measured by vMRI:  see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), (Aβ(1-40), total tau (t-tau), and p-tau will be measured in 
subjects who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and 
activity in CSF may also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) may also be 
evaluated in plasma or CSF. (revised per Amendment 04)  Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will 
be approached to consider reconsenting to postrandomization CSF sample collection even if they are 
beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
(revised per Amendment 04)
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group.  (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses. (revised per Amendments 02 and 05)
Apolipoprotein E (ApoE) and N-acetyltransferase 2 (NAT2) genotyping/phenotyping will be 
conducted.  ApoE4 homozygous or heterozygous status versus non-carriers and NAT2 status will be 
used in the statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA sequence 
variability on the absorption, distribution, metabolism, and elimination of elenbecestat, development 
of adverse events (AEs), as well as the underlying AD. Variations in elenbecestat exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
Page 43 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 17 of 164
single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments (Core Study)
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and serious adverse events (SAEs), monitoring of hematology, blood chemistry, 
and urinalysis, measurement of vital signs, regular ECGs, physical and neurological examinations, 
and centralized dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a more detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the 
frequency and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the 1st month, every 2 weeks for the next 2 months 
(Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be 
monitored every 3 months until the end of the Treatment Period and at all 4 Follow-Up Visits at 2, 4, 
8, and 12 weeks after the last dose of study drug.  Serum IgG, IgA, and IgM will be monitored 
monthly for the 1st 3 months, at 6, 12, and 18 months, and at the Follow-Up Visits that occur 4, 8, 
and 12 weeks after the last dose of study drug. (revised per Amendment 04)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments 
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers or informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects from whom CSF samples were collected (revised per 
Amendments 02 and 04).  These samples may be tested for exploratory biomarkers associated with 
study drug or disease, or in the event that a subject develops AEs that warrant further investigation 
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected infective 
agents before treatment with study drug).
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurologic examinations will be performed at Baseline, at 6, 12, and 18 months, and at the 4- and 
12-week Follow-up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  The neurologic examinations will include 
muscle strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Smell Identification Test, as well as other parts of the CNS. (revised per Amendment 04)
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
Page 44 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 18 of 164
regular intervals throughout the Treatment and Follow-up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline.
An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Efficacy Assessments (Extension Phase) (revised per Amendment 07)
MMSE: A 30-point scale that measures orientation to time and place, registration, immediate and 
delayed recall, attention, language, and drawing.
FAQ:  The FAQ has 10 items concerned with performing daily tasks necessary for independent 
living.  The caregiver or informant provides performance ratings on 10 complex activities of daily 
living performed within the preceding 4 weeks.  
vMRI: vMRI will be used to evaluate disease modification, including the changes from the Core 
Study Baseline and the Extension Phase Baseline in terms of the measured hippocampal volume 
based upon the centralized measurement of the structure on repeated MRIs.
Pharmacodynamic and Other Biomarker Assessments (Extension Phase) 
(revised per 
Amendment 07)
Exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) will be evaluated in plasma.
Safety Assessments (Extension Phase) (revised per Amendments 07 and 08)
All subjects will be assessed for their eligibility for the Extension Phase at Visit 21. Where 
applicable, results of the safety assessments (including laboratory assessment, physical examination, 
and neurologic examination) conducted during Visit 20 will serve as Visit 21 values for the Extension 
Phase with the following exceptions:
if Visit 21 occurs more than 10 days after Visit 20, all 
laboratory safety assessments and vital signs must be repeated.
Routine safety assessments will include the monitoring and recording all AEs and SAEs, monitoring 
of hematology, blood chemistry, and urinalysis, measurement of vital signs, regular ECGs, and 
physical, dermatologic and neurologic examinations at regular intervals.  
There will be no centralized dermatological assessments in the Extension Phase. Dermatologic 
review will be conducted as part of the physical examination. These assessments will specifically 
include evaluation of any areas of depigmentation or drug-induced vitiligo as well as any evidence of 
rash. Subjects will also be questioned by the investigator at each visit to identify any changes that 
might represent a drug-induced rash/reaction or infection. Subjects and their caregivers or informants
will be instructed to contact the investigator if they see any lesions or other symptoms that might be 
associated with a drug-induced rash/reaction or infection, so that such AEs can be reviewed promptly.
Full neurologic examinations will be performed at the start of the Extension Phase (Visit 20 or 21) 
and at every 6 months during the first 24 months of the Extension Phase Treatment Period and every 
12 months thereafter.  An additional neurologic examination will also be performed at the final 
Follow-up Visit. The neurologic examinations will include muscle strength testing and assessment of 
cranial nerves including olfaction, with the use of the Brief Smell Identification Test, as well as other 
parts of the CNS.  
Complete blood counts and percentages will be measured (by a centralized laboratory) every 
scheduled visit. Lymphocyte subset absolute counts and percentages will also be measured during the 
first 12 months of the Extension Phase (by a central laboratory) and the results will be reviewed by 
the sponsor and the members of the DSMB only.
Page 45 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 19 of 164
PBMCs will be collected at Extension Phase Baseline (Visit 21), 6 months (Visit 26), 12 months 
(Visit 28), and 24 months (Visit 32) for exploratory immunomodulatory and immune-based analyses.  
Blood samples will be collected and stored; these samples may be used for further exploratory 
biomarker analyses, and/or, in the event that the subject develops treatment-emergent adverse events 
that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to 
determine whether the subject already had prior exposure to any suspected infective agents.
Safety brain MRI and vMRI assessments will be performed at Month 24 and Month 48 of the 
Extension Phase Treatment Period (Visits 32 and 38, or ED Visit). Subjects who discontinue early 
from the Extension Phase will have safety brain MRI and vMRI assessments at the ED Visit if these 
assessments have not already been performed during the preceding 90 days.  Additional safety MRI 
scans are to be performed as clinically necessary.  MRI acquisition and interpretation will be 
organized centrally to ensure reproducibility and consistency between units involved.  
Assessment of suicidality using the C-SSRS, will be performed at the start of the Extension Phase 
(Visit 21) and at Month 24 (Visit 32) and Month 48 (Visit 38) of the Extension Phase Treatment 
Period.  Subjects who discontinue early from the Extension Phase will have assessments of 
suicidality using C-SSRS at the ED Visit.  Clinical assessment of suicidality, collected from both the 
subject and the caregiver or informant, will be performed at every scheduled interim safety visit that 
do not include administration of the C-SSRS.  At these visits, a positive suicidality assessment (ie, a 
“yes” response on the clinical assessment of suicidal thinking and behavior) from the subject or the 
caregiver/informant on the clinical assessment of suicidality will trigger the C-SSRS to be 
administered.  (revised per amendment 08)
Bioanalytical Methods
Plasma and CSF elenbecestat concentrations will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and postscreening analysis of CSF Aβ(1-42), Aβ(1-40), 
t-tau, and p-tau will be performed using commercially available ELISAs.  (revised per 
Amendment 04)
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
Study Endpoints (Core Study)
Primary Endpoint

Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) 
and SAEs, laboratory parameters, vital signs, and ECG parameters (revised per Amendment 05) 
Secondary Endpoints 
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after at least 4 weeks and 
18 months of treatment
Page 46 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 20 of 164

The population PK parameters of elenbecestat in CSF and plasma, including the effect of intrinsic 
and extrinsic factors (including NAT2 phenotype)  
Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
Change from baseline in:

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment 

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and during 
posttreatment follow-up

CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 18 months of treatment 
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and 18 months as 
measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain amyloid 
levels

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months:  
ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ 
Study Endpoints (Extension Phase) (revised per Amendments 07 and 08)
Primary Endpoint

Safety endpoints: AE, vital sign, ECG, physical examination, clinical laboratory test, any 
relevant test of cognitive function to evaluate decline, and MRI parameters (microhemorrhage, 
vasogenic edema, and other clinically significant abnormalities).
Secondary Endpoints 
Changes from Core Study and Extension Phase baselines in:

MMSE and FAQ at each visit assessed in the Extension Phase

Plasma amyloid measurements at 12, 24, 36, and 48 months of Extension Phase treatment

vMRI parameters including, but not limited to, total hippocampal volume, left and right 
hippocampal volume, whole brain volume, and total ventricular volume at 24 and 48 months of 
Extension Phase treatment 
Analysis Sets (Core Study)

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postdose exploratory efficacy measurement.  (revised 
per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable elenbecestat plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at least 
Page 47 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 21 of 164
1 posttreatment PD measurement.
Analysis Sets (Extension Phase) (revised per Amendment 07)

The Extension Phase Safety Analysis Set (OLE-SAS) is the group of subjects who receive at least 
1 dose of study drug during the Extension Phase and who had any on-therapy safety data during 
the Extension Phase. (revised per Amendment 08). 

The Extension Phase Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 1 
dose of study drug during the Extension Phase and have at least 1 postdose efficacy assessment 
during the Extension Phase.

The Extension Phase PD Analysis Set (OLE-PD) is the group of subjects who have at least 1 
posttreatment PD measurement during the Extension Phase.
Efficacy and Biomarker Analyses (revised per Amendment 05)
Analysis for the Primary Endpoint (Core Study)
There is no primary efficacy endpoint.  (revised per Amendment 05)
Analysis for the Secondary Endpoints (Core Study)
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:
Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 18 months.  Data 
from early discontinuations will also be included.  (revised per Amendment 05)
Analysis for Exploratory Endpoints (Core Study)
(revised per Amendments 01, 02, 04, and 05)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) 
from 4 weeks and up to 18 months of treatment

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months 
of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 months of 
treatment, and during posttreatment follow-up

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by vMRI 

Change from baseline in left and right hippocampal, whole brain, and total ventricular volume at 
6, 12, and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid levels
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, CBB, and 
FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
Pharmacokinetic Analyses (Core Study)
Page 48 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 22 of 164
The PK Analysis Set will be used for elenbecestat concentration listings and for summaries of 
elenbecestat concentrations in plasma and CSF by dose and day. Elenbecestat metabolite PK data 
may also be listed and summarized.  (revised per Amendment 05)
A population PK approach will be used to characterize the plasma PK of elenbecestat. For this 
approach, plasma PK data from this study will be pooled with relevant data from Phase 1 studies.  As 
appropriate, the effect of covariates on the PK of elenbecestat will be evaluated.  The PK model will 
be parameterized for oral clearance (CL/F) and apparent volume of distribution (Vz/F) for 
elenbecestat. Derived exposure parameters such as steady state area under the concentration time 
curve (AUCss) and average concentration (Cavg) of elenbecestat and other derived parameters will be 
calculated from the model using the individual estimates parameterized for oral clearance and dosing 
history. (revised per Amendment 04)
Pharmacodynamic Analyses (Core Study)
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma 
biomarkers, MRI endpoints).  The percentage change from baseline in CSF Aβ(1-x), Aβ(1-40), 
Aβ(1-42), t-tau, p-tau, and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months will be analyzed and presented graphically.  (revised per Amendments 04 and 05)  
Baseline levels and changes in t-tau and p-tau will be correlated with changes in CSF Aβ(1-42), 
imaging markers, and ApoE4 status.  Summary statistics for CSF biomarkers will be assessed for 
evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses (Core Study)
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
elenbecestat dose, plasma and CSF exposure will be initially explored graphically and any emergent 
relationship will be explored through population PK/PD modeling.  Additionally, the relationship 
between CSF exposure to elenbecestat and the change from baseline for 18 months in the ADAS-cog,
the CDR, and the MMSE will be explored graphically.  (revised per Amendments 04 and 05)
Additionally, the relationship between plasma exposures of elenbecestat and select lymphocyte 
parameters will be explored graphically, and any emergent relationship will be explored using 
population-based modeling methods. (revised per Amendment 04)
Pharmacogenomic Analyses (Core Study)
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses (Core Study)
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, vital sign measurements, and cognitive decline 
assessment such as CBB will be summarized by treatment group using descriptive statistics.  (revised 
per Amendment 05)
Lymphocyte Subsets
Page 49 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 23 of 164
Lymphocyte subsets, including but not limited to, CD4 (T helper cells), CD8 (cytotoxic T cells), 
CD19 (B cells), CD16/CD56 (natural killer cells), and CD14 (macrophages) and regulatory T cells 
will be summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets 
and the mean change from baseline in lymphocyte subsets will also be displayed graphically over 
time by dose.  
Serum IgG, IgM, IgA will be measured and summarized in the same manner as other laboratory 
parameters. (revised per Amendment 04)
Interim Analyses Core Study
In order to make decisions about the remainder of the study as well as the full elenbecestat clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and 
perform interim analyses of these data.  Investigators, other clinical site staff, subjects, 
caregivers/informants and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when 60 subjects (±20%) have completed 12 weeks 
of treatment (or discontinue study drug early).  (revised per Amendments 01, 03, 04, and 05) 
Stratification Core Study
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no).  (revised per Amendment 01)
Efficacy Analyses (Extension Phase)  (revised per Amendments 07 and 08)
The following secondary efficacy endpoints will be summarized by descriptive statistics and/or 
graphs, using OLE-FAS:

Changes from Core Study and Extension Phase baselines in MMSE and FAQ scores

Changes from Core Study and Extension Phase baselines in vMRI parameters including, but not 
limited to, total hippocampal volume, left and right hippocampal volume, whole brain volume, 
and total ventricular volume at 24 and 48 months 
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis.
Pharmacodynamic Analyses (Extension Phase)  (revised per Amendments 07 and 08)
The OLE PD Analysis Set will be used for the summaries and analyses of PD biomarkers. The 
percentage change in plasma amyloid measurements from Core Study and Extension Phase baselines 
to 12, 24, 36, and 48 months of Extension Phase treatment will be analyzed and presented 
graphically.
Safety Analyses (Extension Phase) (revised per Amendment 07)
Safety analysis will be performed similarly to the Core Study. Evaluations of safety will be 
performed on the OLE-SAS.  The incidence of AEs (including changes from baseline in physical and 
neurological examinations, and dermatological assessments), out-of-normal-range laboratory safety 
test variables, abnormal ECG findings, out-of-range vital signs, suicidality (C-SSRS and clinical 
assessment of suicidality), and changes from baseline in laboratory safety test variables, ECGs, safety 
MRI, vital sign measurements, and cognitive decline assessment such as MMSE will be summarized 
by using descriptive statistics.  
Page 50 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 24 of 164
Sample Size Rationale
A total of 15 subjects per dose is deemed sufficient to derive adequate safety and PK/PD data to aid 
in the selection of appropriate doses and the design of the Phase 3 studies that may be planned 
subsequently.  (revised per Amendment 04)  Based upon the selection of the elenbecestat 50-mg 
dose for the Phase 3 studies, subjects randomized to the active treatment arms will be re-assigned to 
the selected 50-mg dose for further evaluation. (revised per Amendment 06)
Page 51 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 25 of 164
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................25
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................30
5
ETHICS............................................................................................................................33
5.1
Institutional Review Boards/Independent Ethics Committees ..............................33
5.2
Ethical Conduct of the Study.................................................................................33
5.3
Subject Information and Informed Consent...........................................................34
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................36
7
INTRODUCTION ...........................................................................................................37
7.1
Results of Interim Evaluations...............................................................................38
7.2
Nonclinical and Clinical Safety Data.....................................................................38
8
STUDY OBJECTIVES....................................................................................................41
8.1
Primary Objective..................................................................................................41
8.2
Secondary Objectives.............................................................................................41
8.3
Exploratory Objectives ..........................................................................................41
9
INVESTIGATIONAL PLAN..........................................................................................43
9.1
Overall Study Design and Plan..............................................................................43
9.1.1
Prerandomization Phase...............................................................................45
9.1.1.1
Screening Period..................................................................................46
9.1.1.2
Baseline Period ....................................................................................47
9.1.2
Randomization Phase...................................................................................48
9.1.2.1
Treatment Period..................................................................................48
9.1.2.2
Early Discontinuation ..........................................................................49
9.1.2.3
Follow-Up Period.................................................................................49
9.1.3
Extension Phase ...........................................................................................49
9.1.3.1
Early Discontinuation ..........................................................................50
9.1.3.2
Follow-Up............................................................................................50
9.2
Discussion of Study Design, Including Choice of Control Groups.......................50
9.2.1
Overview......................................................................................................50
9.2.2
Rationale for Study Population....................................................................51
9.2.3
Rationale for Clinical Endpoints..................................................................52
9.2.4
Rationale for Biomarkers.............................................................................53
9.2.4.1
Overall Rationale .................................................................................53
9.2.4.2
Soluble Biomarkers in CSF .................................................................53
Page 52 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 26 of 164
9.2.4.3
Amyloid PET .......................................................................................54
9.2.4.4
vMRI....................................................................................................54
9.2.5
Clinical Risks and Mitigation Strategy........................................................55
9.3
Selection of Study Population................................................................................57
9.3.1
Inclusion Criteria .........................................................................................57
9.3.2
Exclusion Criteria ........................................................................................59
9.3.3
Removal of Subjects from Therapy or Assessment.....................................63
9.4
Treatments..............................................................................................................66
9.4.1
Treatments Administered.............................................................................66
9.4.2
Identity of Investigational Product...............................................................67
9.4.2.1
Chemical Name and Formula of Elenbecestat (E2609).......................67
9.4.2.2
Comparator Drug .................................................................................67
9.4.2.3
Labeling for Study Drug......................................................................68
9.4.2.4
Storage Conditions...............................................................................68
9.4.3
Method of Assigning Subjects to Treatment Groups...................................68
9.4.4
Selection of Doses in the Study...................................................................68
9.4.5
Selection and Timing of Dose for Each Subject..........................................70
9.4.6
Blinding........................................................................................................70
9.4.7
Prior and Concomitant Therapy...................................................................71
9.4.8
Treatment Compliance.................................................................................73
9.4.9
Drug Supplies and Accountability...............................................................73
9.5
Study Assessments.................................................................................................75
9.5.1
Assessments.................................................................................................75
9.5.1.1
Demography.........................................................................................75
9.5.1.2
Baseline Assessments ..........................................................................75
9.5.1.2.1
Medical History and Physical Examinations.................................75
9.5.1.2.2
Viral Testing ..................................................................................75
9.5.1.2.3
B12 Testing....................................................................................75
9.5.1.2.4
TB Exposure Testing .....................................................................76
9.5.1.2.5
Urine Drug Testing ........................................................................76
9.5.1.3
Efficacy Assessments...........................................................................76
9.5.1.3.1
Psychometric Assessments ............................................................76
9.5.1.3.2
Volumetric MRI.............................................................................77
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................78
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................78
9.5.1.4.1
Pharmacokinetic Assessments .......................................................78
Page 53 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 27 of 164
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................79
9.5.1.5
Safety Assessments..............................................................................81
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..81
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................84
9.5.1.5.3
Laboratory Measurements .............................................................85
9.5.1.5.4
Vital Signs and Weight Measurements..........................................87
9.5.1.5.5
Physical Examinations...................................................................87
9.5.1.5.6
Electrocardiograms ........................................................................87
9.5.1.5.7
Safety MRI.....................................................................................88
9.5.1.5.8
Dermatologic Assessment..............................................................89
9.5.1.5.9
Neurologic Examination................................................................89
9.5.1.5.10
Pregnancy Test...............................................................................90
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................90
9.5.1.5.12
Biomarker Samples........................................................................90
9.5.1.5.13
Ophthalmic Examinations..............................................................90
9.5.2
Schedule of Procedures/Assessments ..........................................................91
9.5.2.1
Schedule of Procedures/Assessments ..................................................91
9.5.2.2
Description of Procedures/Assessments Schedule...............................98
9.5.3
Appropriateness of Measurements...............................................................99
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................99
9.5.4.1
Reporting of Serious Adverse Events..................................................99
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .....................................................................................100
9.5.4.3
Reporting of Events Associated with Special Situations...................101
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................101
9.5.4.3.2
Reporting of Study-Specific Events.............................................101
9.5.4.4
Expedited Reporting ..........................................................................101
9.5.4.5
Breaking the Blind.............................................................................102
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................102
9.5.5
Completion/Discontinuation of Subjects...................................................102
9.5.6
Abuse or Diversion of Study Drug ............................................................103
9.5.7
Confirmation of Medical Care by Another Physician ...............................103
9.6
Data Quality Assurance .......................................................................................103
9.6.1
Data Collection ..........................................................................................103
Page 54 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 28 of 164
9.6.2
Clinical Data Management ........................................................................104
9.7
Statistical Methods...............................................................................................104
9.7.1
Statistical and Analytical Plans..................................................................104
9.7.1.1
Study Endpoints.................................................................................104
9.7.1.1.1
Primary Endpoint.........................................................................104
9.7.1.1.2
Secondary Endpoints ...................................................................104
9.7.1.1.3
Exploratory Endpoints .................................................................105
9.7.1.2
Definitions of Analysis Sets...............................................................105
9.7.1.3
Subject Disposition............................................................................105
9.7.1.4
Demographic and Other Baseline Characteristics .............................106
9.7.1.5
Prior and Concomitant Therapy.........................................................106
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05) ......107
9.7.1.6.1
Primary Efficacy Analysis...........................................................107
9.7.1.6.2
Secondary Efficacy Analyses ......................................................107
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................107
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................108
9.7.1.7.1
Pharmacokinetic Analyses...........................................................108
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................108
9.7.1.8
Safety Analyses..................................................................................109
9.7.1.8.1
Extent of Exposure.......................................................................109
9.7.1.8.2
Adverse Events ............................................................................110
9.7.1.8.3
Laboratory Values........................................................................111
9.7.1.8.4
Vital Signs....................................................................................112
9.7.1.8.5
Electrocardiograms ......................................................................112
9.7.1.8.6
Other Safety Analyses..................................................................112
9.7.2
Determination of Sample Size ...................................................................113
9.7.3
Interim Analysis.........................................................................................113
9.7.4
Other Statistical/Analytical Issues .............................................................113
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................113
10
REFERENCE LIST .......................................................................................................114
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....118
11.1
Changes to the Protocol .......................................................................................118
11.2
Adherence to the Protocol....................................................................................118
11.3
Monitoring Procedures.........................................................................................118
11.4
Recording of Data................................................................................................119
11.5
Identification of Source Data...............................................................................119
Page 55 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 29 of 164
11.6
Retention of Records............................................................................................120
11.7
Auditing Procedures and Inspection....................................................................120
11.8
Handling of Study Drug.......................................................................................120
11.9
Publication of Results ..........................................................................................121
11.10 Disclosure and Confidentiality ............................................................................121
11.11 Discontinuation of Study .....................................................................................121
11.12 Subject Insurance and Indemnity.........................................................................122
12
APPENDICES ...............................................................................................................123
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................64
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................65
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................69
Table 4
Clinical Laboratory Tests...........................................................................86
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™..................................87
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................91
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................94
Table 8
Summary of Blood and CSF Sample Volumes..........................................98
LIST OF IN-TEXT FIGURES
Figure 1
Design of Core Study E2609-G000-202....................................................44
Figure 2
Assessments to be Performed at Screening by Tier...................................47
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................123
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........126
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 138
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................141
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................144
Appendix 6
Extension Phase .......................................................................................148
Page 56 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 30 of 164
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg,
1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
AE
adverse event
ApoE
apolipoprotein E
AUC(0-24h)ss
area under the concentration × time curve at steady state from time zero 
to 24 hours
AUCss
steady state area under the concentration × time curve
BACE1
Beta (β)-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
Cavg
average concentration
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carboxyesterase-2
CFR
Code of Federal Regulations
CL/F
oral clearance  
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
DSMB
data safety monitoring board
eCRF
electronic case report form
Page 57 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 31 of 164
Abbreviation
Term
ED
early discontinuation
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
mild cognitive impairment due to Alzheimer’s disease/ prodromal 
Alzheimer’s disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
Page 58 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 32 of 164
Abbreviation
Term
NIA-AA
National Institute on Aging-Alzheimer’s Association
OLE
Open-label Extension
OLE-SAS
Extension Phase Safety Analysis Set
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
Vz/F
apparent volume of distribution
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 59 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 33 of 164
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 Registration of 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 associate [CRA][s], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 60 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 34 of 164

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.  
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 61 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 35 of 164
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for from 4 weeks and up to 18 months 
(or at Early Discontinuation [ED]) during the Core Study.  This consent for CSF sample 
collection is not required for study eligibility. (revised per Amendments 02 and 05)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects and will be via a 
separate, optional CSF consent form for the study.  (revised per Amendment 04)
Page 62 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 36 of 164
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 35 investigational sites in the United States.
(revised per 
Amendments 01, 02, 04, and 05)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 63 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 37 of 164
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010;
Lu, et al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, 
thus accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Rosen, et al., 1984; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
Elenbecestat (E2609) is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have 
shown that after oral dosing, elenbecestat inhibits the production of Aβ40 and Aβ42 in brain 
(rat and guinea pig) and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and 
monkey). In humans, elenbecestat has been shown to inhibit BACE1 enzyme activity in CSF 
and lower the levels of Aβ, including amyloid beta monomer from amino acid 1 to x (Aβ[1-
x]), Aβ(1-40) and Aβ(1-42), in CSF both in vitro and in vivo.  See the Investigator’s 
Brochure for additional information.  The target indication for elenbecestat is therefore 
treatment and disease modification of AD.  
The present clinical study is a Phase 2 study for the elenbecestat program, and is designed to 
establish safety in subjects with MCI due to AD/Prodromal AD (referred to as 
MCI/Prodromal throughout the protocol) and in subjects with mild to moderate AD.  (revised 
per Amendment 05)  This study will include a Core Study of approximately 32 months 
(including the Prerandomization and Randomization Phases) and an Open-label Extension 
Phase of up to 51 months. (revised per Amendments 07 and 08)  Results from the Core Study 
Page 64 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 38 of 164
will guide both the decision to move into Phase 3 development and the selection of the dose 
strengths to be taken into Phase 3.  
In the MCI/Prodromal and mild to moderate AD population, the Core Study will compare 
placebo and 3 oral doses of elenbecestat (5, 15, and 50 mg) administered once daily (QD) for 
18 months.  (revised per Amendment 05)  
The
Core Study will include interim evaluations
of the pharmacokinetic (PK), 
pharmacodynamic (PD), safety, and tolerability of chronic dosing with elenbecestat. (revised 
per Amendment 05)  Furthermore, there will be close monitoring of safety by an independent 
data safety monitoring board (DSMB), including a formal safety review as soon as the 
randomized subjects (n=60, ±20%) have completed at least 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  (revised per Amendments 04 and 
05) The study also includes a number of exclusion criteria, specific blinded safety monitoring 
procedures and safety criteria for discontinuation of study drug in light of the preclinical and 
clinical safety data collected to date following administration of elenbecestat.  
The Extension Phase will evaluate the long-term safety and tolerability of elenbecestat; a 
detailed description of the Extension Phase is provided in Appendix 6. (revised per 
Amendment 07)
7.1
Results of Interim Evaluations
(revised per Amendment 06)
Unblinded interim evaluations of the safety and tolerability of elenbecestat
suggested 
favorable safety at all doses of elenbecestat. 
Additionally, analyses of the PD effects 
(reduction from baseline in CSF Aβ levels) of elenbecestat 5, 15, and 50 mg per day have 
indicated that elenbecestat 50 mg per day produced relatively high levels of CSF Aβ 
reduction (greater than 50%). Based on the results of these analyses, elenbecestat 50 mg per 
day has been selected as the dose for Phase 3 development. 
As elenbecestat 5 and 15 mg per day will not be advanced clinically, subjects initially 
randomized to the elenbecestat 5 and 15 mg per day treatment arms will be re-assigned in a 
blinded manner to the elenbecestat 50 mg treatment arm provided that they will have at least 
12 weeks of treatment remaining in the Randomization Phase. The purpose of this dose 
re-assignment is to further characterize the safety and tolerability of elenbecestat 50 mg.  
7.2
Nonclinical and Clinical Safety Data
The toxicity of elenbecestat has been evaluated in oral repeated-dose toxicology studies of 
up to 26 weeks duration in rats and 39 weeks in cynomolgus monkeys.  Nonclinical findings 
of note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by elenbecestat in a 
Page 65 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 39 of 164
clinical setting.  Further details of the nonclinical data to date with elenbecestat can be found 
in the Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Study E2609-A001-002 (Study 002) was a randomized, double-blind and placebo-controlled, 
multiple ascending dose (MAD) study in healthy male and female subjects aged 50 to 85 
years.  CSF was collected before and following the 14 days of dosing so as to assess the PK 
levels of elenbecestat (E2609) and the PD effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of elenbecestat.  It also investigated the effects of elenbecestat on the PK 
properties of digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 (Study 005) was an open label, single-dose study to determine the 
metabolism and elimination of [14C]-elenbecestat (E2609) in healthy male subjects (aged 
18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of elenbecestat under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with elenbecestat.
The clinical safety data are 
described in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with elenbecestat.  In
elderly subjects treated with 50 mg of elenbecestat, tolerability was comparable to younger 
subjects.  There were no specific AEs in elderly subjects which were evidently more frequent 
than in younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or ECG
parameters.  The 800 mg (maximum) dose was associated with a small increase of QTc 
interval calculated using Fridericia’s formula (QTcF) from baseline (14.9 msec at 4 hours 
postdose), consistent with nonclinical findings.  Overall the data suggested that a single dose 
Page 66 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 40 of 164
of elenbecestat might reduce some lymphocyte subsets (eg, CD4 [T helper cells], CD8 
[cytotoxic T cells]) but the effects were highly variable across doses and the findings were 
not conclusive.  There were no trends to suggest that elenbecestat altered immunoglobulin
(Ig) levels. There were no clinical manifestations in terms of primary infections or relapse of 
latent infections in subjects who received single doses of elenbecestat.  A single dose of 
elenbecestat up to 800 mg is not considered to pose clinical safety concerns with regard to 
immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, elenbecestat administered at doses of 200 and 400 mg was associated 
with reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts 
at Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
elenbecestat on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP]3A4 and carboxyesterase-2 [CES2]) increased by
approximately 70% the AUC of elenbecestat.  Consequently, strong inhibitors of CYP3A4 
will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of elenbecestat.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of elenbecestat
when coadministered with elenbecestat but not when dosed at least 2 hours apart from 
elenbecestat. Elenbecestat (which inhibits the P-glycoprotein 1 transporter) did not affect the 
PK properties of digoxin.  Nonclinical studies also indicated that other CYP pathways apart 
from CYP3A4 would not be major pathways of metabolism of elenbecestat. Therefore, on 
the basis of drug interaction considerations, the only restriction of concomitant medications 
is that for strong inhibitors of CYP3A4. 
Page 67 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 41 of 164
8
STUDY OBJECTIVES
Objectives for the Extension Phase are provided in Appendix 6. (revised per Amendment 07)
8.1
Primary Objective
(revised per Amendment 05)
The primary objective is:  

To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with elenbecestat in MCI/Prodromal subjects and in subjects 
with mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendments 02 and 05)

To characterize the plasma and CSF PK of elenbecestat

To assess the effects of elenbecestat on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and
at 18 months of treatment 
8.3
Exploratory Objectives
(revised per Amendments 01, 02, 04, and 05)  
The exploratory objectives are:  

To explore the effects of elenbecestat compared on CSF Aβ(1-40) and BACE1 
measurements from 4 weeks and up to 18 months of treatment 

To explore the effects of elenbecestat compared with placebo on various biomarkers.  
Biomarkers to be explored may include, but not limited to:  
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
Page 68 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 42 of 164

To explore the effects of elenbecestat compared with placebo on clinical status at various 
time points during 18 months of treatment, and during posttreatment follow-up by 
assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of elenbecestat on measured 
clinical efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF amyloid 
isoforms, brain amyloid, and vMRI 

To explore relationships between both elenbecestat dose and exposure, with PD and 
safety endpoints 
Page 69 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 43 of 164
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study with an Extension Phase of up to 51 months in subjects with 
MCI/Prodromal AD or mild to moderate AD.  (revised per Amendments 01, 07, and 08)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists of 3 phases: Prerandomization, Randomization, and Extension Phase.  
The Prerandomization and Randomization Phases are referred to as the Core Study 
throughout the protocol.  (revised per Amendment 07).  
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and
Figure 2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-up (post last dose; 12 weeks).
All subjects (MCI/Prodromal and mild to moderate AD) will initially be randomized 1:1:1:1 
to 4 treatment groups (5, 15, or 50 mg elenbecestat or placebo) (revised per Amendments 01
and 05).  Upon implementation of Amendment 06, at the next regularly scheduled visit, 
subjects receiving elenbecestat 5 or 15 mg who have not yet completed Visit 17 (Week 66), 
will be re-assigned in a blinded manner to elenbecestat 50 mg for the remainder of the 
Treatment Period.  In order to maintain the blind, all subjects who have not yet had Visit 17 
will go through the same procedures with the placebo-randomized subjects continuing to 
receive placebo and those randomized to elenbecestat 50 mg continuing to receive 50 mg.  
(revised per Amendment 06)
All subjects who complete 18 months of treatment and 12 weeks of follow-up in the Core 
Study and who satisfy the entry criteria for the Extension Phase are eligible to enter the 
Extension Phase.  During the Extension Phase, subjects will receive elenbecestat 50 mg daily 
for up to 48 months (4 years). (revised per Amendment 08)
Page 70 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 44 of 164
An overview of the Core Study design is presented in Figure 1.
Figure 1
Design of Core Study E2609-G000-202
(revised per Amendments 01, 02, 05, and 06)
R = randomization, AD = Alzheimer’s disease, MCI = mild cognitive impairment
This study will be limited to approximately 35 sites in the United States, with approximately 
60 (±20%) eligible subjects randomized at Visit 3, 1:1:1:1 to 4 treatment groups within each 
clinical cohort.  In addition to the placebo group, 3 doses of elenbecestat will be used to 
reduce CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from 
baseline, respectively, at steady state.  PK/PD modeling shows these doses should achieve 
these targets when administered QD with food and will be evaluated based on the 4-week (or 
later) assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement (see Section 9.4.4 ). (revised per Amendments 01, 02, 04, and 05) Safety data 
will be monitored in a blinded fashion on a regular basis.  
In addition, approximately every 3 months from the time the 1st subject is randomized into
the study through the time the last subject is randomized, an independent DSMB (including 
at least 1 immunologist) will review all safety data in an unblinded manner. (revised per 
amendment 06) The DSMB will make recommendations to Eisai after each review as to 
whether any change(s) to the study are necessary.  (revised per Amendments 01, 04, and 05)  
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
Page 71 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 45 of 164
Interim analyses of the elenbecestat plasma PK for all subjects and the elenbecestat CSF PK 
and PD profiles will be performed on baseline data and samples collected after at least 
4 weeks of treatment in the Core Study.  (revised per Amendment 05 and 07)  Refer Section 
9.7.3 for more detail.  These data will be used to evaluate the CSF PD effects of elenbecestat
doses, where PD is measured as reductions from baseline in CSF Aβ(1-x) levels (see 
Section 9.4.4).
The median and mean percentage change from baseline in CSF Aβ(1-x) 
measured after 4 weeks or more of treatment for each dose of elenbecestat and the 90% CI 
for the median will be derived. In addition, exploratory PK/PD modeling will be conducted.  
This PK/PD modeling will use the observed PK and PD data and will relate the average 
steady state plasma concentration of elenbecestat to steady state CSF Aβ(1-x) percentage 
reduction from baseline determined after at least 4 weeks of dosing.  (revised per 
Amendments 01, 02, 03, and 04)
Once subjects have completed at least 12 weeks of treatment in the Core Study (or 
discontinued study drug early), an interim safety analysis will be conducted by Eisai and the 
DSMB.  (revised per Amendments 01, 04, and 05)  At the completion of this interim safety 
review, the frequency of subsequent unblinded safety reviews will be re-evaluated by the 
DSMB and the sponsor and this information will be provided in the DSMB charter. (revised 
per Amendment 06) Subjects will continue study drug while the DSMB reviews all the 
available safety data.  (revised per Amendment 05)  At the time of this interim safety 
analysis, some subjects will have more than 12 weeks of safety data.  
Interim analyses are planned and are discussed in Section
9.7.3.
(revised per 
Amendment 03)
Based on the results of the interim analyses, the elenbecestat 50 mg dose has been chosen as 
the clinical dose for the Phase 3 studies.  In order to collect additional safety data for 
elenbecestat 50 mg, subjects randomized to elenbecestat 5 or 15 mg in this study will be re-
assigned to elenbecestat 50 mg if and only if these subjects have at least 12 weeks of 
treatment remaining in the Randomization Phase following study drug dose re-assignment.  
Therefore, subjects who completed Visit 17 assessments before the implementation of 
Amendment 06 will remain on their original randomized dose.  As study drug dose re-
assignment will occur in a blinded manner, a 4-week interim safety assessment following 
study drug re-assignment will be required for all subjects.  (revised per Amendment 06)
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
Page 72 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 46 of 164
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization, the clinician will provide a judgment on the classification of a subject as 
either MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This 
judgment may be discussed and reviewed with the sponsor or sponsor’s representative, as 
necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
Screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
Page 73 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 47 of 164
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.
(revised per Amendment 02)  
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Page 74 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 48 of 164
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination (including 
the Brief Smell Identification Test [Sensonics Inc.]) will be performed.  (revised per 
Amendment 04) A urine pregnancy test will be conducted for females of childbearing 
potential.  Blood will be collected from all subjects for clinical chemistry and hematology, 
lymphocyte subset analyses, Ig analyses, and PD assessments.  Blood samples will be 
collected and stored for determination of a subject’s previous exposure to infective pathogens 
in the event of AEs that warrant further investigation occurring at a later point in the study.  
Psychometric assessments will be administered to the subject in the order stated in Table 6.  
The caregiver or informant needs to be present at this visit.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, a CSF sample will be obtained at this 
visit for PK and PD assessments (see Section 9.5.1.4).  (revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the N-acetyltransferase 2 (NAT2) phenotype of subjects 
enrolled in the study (see Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  (revised per Amendment 06)
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
Page 75 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 49 of 164
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug.  Follow-up Visits will also be scheduled 
2, 4, 8, and 12 weeks after the last dose of study drug.  (revised per Amendments 04 and 05)  
9.1.2.3
Follow-Up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 4 posttreatment Follow-up Visits: 2, 4, 8, and 
12 weeks after the last dose of study drug.  If clinically indicated, more frequent safety 
assessments can be conducted as part of Unscheduled (UNS) Visits during the posttreatment 
Follow-up Period.  (revised per Amendment 04)
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Apr 2018.  (revised 
per Amendment 05)

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.1.3
Extension Phase
A complete description of the Extension Phase is provided in Appendix 6; key features are 
summarized below. (revised per Amendment 07)
After completing all Visit 20 follow-up procedures for the Core Study, eligible subjects will 
have the option to participate in an open-label Extension Phase within 4 weeks of Core Study 
Visit 20.  These subjects may transition to the Extension Phase immediately following Visit 
20 (on the same day) if the decision to proceed with the Extension Phase has been made at 
that time.  The medical monitor must be contacted if Visit 21 (start of the Extension Phase) is 
to occur more than 4 weeks after Visit 20.  
For all subjects, assessments performed at Visit 20 may serve as the Visit 21 (start of the 
Extension Phase) results with the following exceptions: laboratory assessments and vital 
signs must be repeated if Visit 21 occurs more than 10 days after Visit 20.
Subjects who are eligible and who consent to participate in the Extension Phase will be 
administered elenbecestat 50 mg daily at Visit 21.  Subjects with pending INR and serum 
pregnancy test results (female subjects of childbearing potential only) but who are otherwise 
qualified may begin Extension Phase dosing at Visit 21; however, these subjects must 
discontinue study drug immediately if either test result meets the exclusion criteria.
During the Extension Phase, safety assessments will continue to be monitored and all AEs 
and SAEs will be recorded.  Vital signs, hematology, blood chemistry, and urine values will 
Page 76 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 50 of 164
be monitored at every scheduled visit. Clinical assessments (MMSE and FAQ) will be 
administered every 3 months for the first 24 months and every 4 months thereafter.  Blood 
for PD analyses will be collected after 12, 24, 36, and 48 months of Extension Phase
treatment. All subjects will be assessed using safety MRIs and vMRI measurements at 24 
and 48 months.  Subjects who discontinue early from the Extension Phase will have safety 
brain MRI and vMRI assessments at the ED Visit if these assessments have not already been 
performed during the preceding 90 days.  If subjects have non-MRI compatible devices fitted 
during treatment, then a computed tomography scan may be utilized to assess safety, if 
deemed appropriate by the investigator. (revised per Amendment 08)
9.1.3.1
Early Discontinuation
Subjects who prematurely discontinue study drug for any reason will undergo an ED Visit 
within 7 days of their last dose of study drug.  Follow-up Visits will also be scheduled 4 and 
12 weeks after the last dose of study drug.  
9.1.3.2
Follow-Up 
All subjects, regardless of whether they complete all 48 months of treatment in the Extension 
Phase or prematurely discontinue study drug will complete 2 posttreatment Follow-up Visits 
at 4 and 12 weeks after the last dose of study drug. If clinically indicated, more frequent 
safety assessments can be conducted as part of UNS Visits during the Extension Phase 
Follow-up Period. 
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The primary objective of the study is to assess the safety and tolerability of daily dosing with 
elenbecestat in subjects with MCI/Prodromal AD and in subjects with mild to moderate AD. 
Immunological and hematological parameters will also be assessed.  (revised per 
Amendment 04)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
Secondary endpoints include CSF PK and plasma PK parameters of elenbecestat based on 
population PK analysis and the percentage reduction of Aβ(1-x) and Aβ(1-42) in CSF 
relative to baseline from 4 weeks and up to 18 months of treatment.
The intrinsic and 
extrinsic factors on the PK characteristics will also be explored.
Page 77 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 51 of 164
Exploratory endpoints include CSF Aβ(1-40) and BACE1 measures as well as CSF 
biomarkers of neuronal degeneration (eg, t-tau and p-tau), volumetric MRI measurements, 
plasma amyloid measurements, brain amyloid levels as measured by amyloid PET and 
clinical assessments.  (revised per Amendment 05) Exploratory endpoints including 
assessments of efficacy, safety, and other biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups (Section 9.7.4)  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred 
(Jack, et al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means elenbecestat is more likely to be efficacious (ie, 
slow disease progression) the earlier in disease progression treatment is started, where 
limited neurodegeneration has occurred and associated clinical deficits are at a minimum.  
However, since the effect of BACE1 inhibition along the AD continuum remains to be 
characterized, elenbecestat will also be evaluated for its profile in mild to moderate stages of 
AD, in the event data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent 
data support the notion of continued progression of amyloid pathology even in these later 
stages of the disease (Hu, et al., 2015), although at a slower pace, suggesting a positive effect 
of BACE inhibition and amyloid beta reduction cannot be ruled out even in the later stages of 
the disease trajectory.  Hence, in this study, elenbecestat will be assessed in subjects with 
disease states ranging from MCI/Prodromal to mild and even moderate AD.  (revised per 
Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as elenbecestat in subjects with more advanced disease such 
as mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, 
Page 78 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 52 of 164
a selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor elenbecestat
in 2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for Clinical Endpoints
The 14-item version of the ADAS-cog will be used in the present study since it is considered 
more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975)
The ISLT is sensitive to memory impairment that characterizes both AD and MCI 
(Lim, et al., 2012a).  In MCI subjects, the magnitude of the impairment observed on the total 
recall and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable 
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with elenbecestat treatment. 
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
Page 79 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 53 of 164
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living.  The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  Volumetric magnetic resonance imaging is discussed in 
Section 9.2.4.4.
9.2.4
Rationale for Biomarkers
9.2.4.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (t-tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.4.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of elenbecestat
on 
Aβ(1-40)+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through
inhibition of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both t-tau and p-tau are sensitive markers of axonal and neuronal degeneration (t-tau) and 
neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel with 
disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have been 
correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful predictors 
of cognitive decline and progression to dementia due to AD.  Rebalancing dysregulated 
amyloid production early in the process may positively affect the neurodegenerative process 
Page 80 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 54 of 164
and thus affect these markers and benefit the disease trajectory.  Therefore, monitoring these 
markers in conjunction with amyloid imaging may provide further supportive evidence of 
disease modifying effects.  (revised per Amendment 04)
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.4.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of elenbecestat on amyloid 
levels in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and 
brain region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment in the 
Core Study (or at ED, providing the subject has received at least 39 weeks of study drug) as 
an exploratory measure of the potential disease-modifying effects of elenbecestat. (revised 
per Amendment 07) Longitudinal amyloid PET imaging will only be conducted on subjects 
with Screening PET scans performed for this study (ie, historical scans cannot be used for the 
longitudinal analyses). (Revised per Amendments 02 and 05)
9.2.4.4
vMRI
Volumetric imaging will be used to evaluate the effects of elenbecestat on rates of atrophy 
across the different dose groups during the Core Study and to provide support that effective 
treatment is associated with modification of disease course (exploratory endpoints in the 
Core Study and Extension Phase).  (revised per Amendments 01 and 07) A large body of 
data has shown that structural MRI reliably tracks disease progression in AD.  Atrophy tends 
to occur preferentially in the lateral temporal and posterior parietal regions during the early 
stages of disease and progresses towards the anterior regions of the brain (frontal cortex) in 
its later stages.  Clinically efficacious doses are predicted to be associated with a slowing in 
the rate of hippocampal atrophy compared with rates observed in the placebo and non-
efficacious dose groups.  Treatment effects on left and right hippocampal, whole brain, and
total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/mL or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
Page 81 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 55 of 164
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF t-tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals during the Core Study and at Month 24 and Month 48 of the
Extension Phase, these relationships and the effects of elenbecestat treatment will be 
explored further.  Subjects who discontinue early from the Extension Phase will have safety 
brain MRI and vMRI assessments at the ED Visit if these assessments have not already been 
performed during the preceding 90 days. (revised per Amendments 07 and 08) Recent 
advances in analysis software have made structural imaging more sensitive to detect small 
changes and able to reliably measure rates of atrophy at these intervals, particularly in the 
posterior parietal and the lateral temporal regions during the early stages of disease (Hua, et 
al., 2009; Hua, et al., 2010).  Given these observations, a demonstration of significant 
slowing or stabilization in the rate of atrophy in response to treatment, compared with
placebo, will offer further support for disease modification.
9.2.5
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with elenbecestat, and to mitigate clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of Core Study treatment 
and 48 months of Extension Phase treatment in this Phase 2 study.
(revised per 
Amendments 07 and 08)  These safety aspects include the following:  

Immunology-related and infection-related exclusion criteria for both the Core Study and 
the Extension Phase (revised per Amendment 07)

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for study drug discontinuation based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) during the Core Study and absolute lymphocytes
during the Extension Phase (revised per Amendment 07)

Safety criteria for study drug discontinuation during the Core Study and Extension Phase 
based on skin rash, reoccurrence of herpes virus infections including any oral herpes, 
genital herpes or shingles, other infections, MRI changes, ECGs, and pregnancy.
(revised per Amendment 07)
Page 82 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 56 of 164
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the Core Study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and dermatological 
assessments at regular intervals. (revised per Amendment 07) AEs that might indicate 
signals of possible drug abuse potential will require a detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned 
on the frequency and impact of these events.  To assess potential immunomodulatory 
effects, peripheral blood mononuclear cells (PBMCs) will be collected at baseline, during 
treatment, and posttreatment of the Core Study and at Extension Phase Baseline (Visit 
21), 6 months (Visit 26), 12 months (Visit 28), and 24 months (Visit 32).  (revised per 
Amendment 08)
As per the communication from the FDA in Aug 2013, there are concerns that 
hypopigmentation of the skin and mucous membranes may occur with BACE1 inhibitory 
drugs.  Although no such effects have been seen with elenbecestat to date, assessments using 
standardized photography will be performed by a central reviewing dermatologist at regular 
intervals during the Core Study. During the Extension Phase, a dermatologic assessment will 
be performed by the investigator at every scheduled visit.  Every assessment will specifically 
include evaluation of any areas of depigmentation or any rash. (revised per Amendment 07)
Dermatological assessments will be supplemented with a specific question to subjects 
regarding skin changes at each visit.  Any such changes could be referred to the central 
reviewing dermatologist, and to a local dermatologist if needed, for further evaluation.  See 
Section 9.5.1.5.8 and Appendix 6 for further details. (revised per Amendment 07)

Baseline and on-study blood will be taken and stored for all subjects during the Core 
Study and Extension Phase.  (revised per Amendment 02 and 07) DNA samples and CSF 
samples (for all subjects who consent to CSF sample collection) will be taken and stored 
during the Core Study. (revised per Amendment 02 and 07)  These samples may be tested 
in the event that a subject develops AEs that warrant further investigation (eg, if a subject 
develops a treatment-emergent infection) (see Section 9.5.1.2.2 and Appendix 6).
(revised per Amendment 07)

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Core Study Treatment Period, and at the final Follow-up Visit during the Core 
Study.  (revised per Amendment 07) MRI assessments will also be performed at 
Month 24 and Month 48 of the Extention Phase Treatment Period.  Subjects who 
discontinue early from the Extension Phase will have safety brain MRI and vMRI 
assessments at the ED Visit if these assessments have not already been performed during 
the preceding 90 days.  In addition, safety brain MRI assessments may be performed as 
an unscheduled assessment if clinically indicated.  (revised per Amendments 07 and 08)
Page 83 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 57 of 164

Full neurologic examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  Details of the neurologic
examination are given in Section 9.5.1.5.9 and Appendix 6. (revised per Amendment 07)

Cognitive decline will be assessed as a safety assessment during the Core Study
(ADAS-cog14, MMSE, and CBB) and during the Extension Phase (MMSE). (revised 
per Amendment 07) Of particular importance will be the assessment of reaction time 
testing using the detection and identification tasks on the CBB during the Core Study.
(revised per Amendment 07)

During the Core Study, an assessment of suicidality using the C-SSRS will be performed 
at Screening, Baseline, and at regular intervals during the Treatment and Follow-up
Period (see Section 9.5.1.5.11). During the Extension Phase, C-SSRS will be performed 
at Visit 21 (start of Extension Phase treatment) and at Month 24 and Month 48 of the 
Extension Phase Treatment Period. Subjects who discontinue early from the Extension 
Phase will have assessments of suicidality using C-SSRS at the ED Visit.  Additional 
clinical assessments of reported suicidal thinking and behavior will be performed by the 
investigator during the Extension Phase at visits that do not include administration of 
C-SSRS (see Appendix 6). (revised per Amendments 07 and 08)

All subjects, regardless of whether they complete all 18 months of treatment or 
prematurely discontinue study drug during the Core Study, will have at least 4
off-treatment Follow-up Visits during the Core Study (2, 4, 8, and 12 weeks after the last 
dose of study drug). Subjects who complete or prematurely discontinue study drug 
during the Extension Phase will have 2 off-treatment Follow-up Visits at 4 and 12 weeks 
after the last dose of study drug. (revised per Amendment 07)

More frequent safety assessments can be made as unscheduled assessments/visits during 
the off-treatment Follow-up Period, if clinically indicated. (revised per Amendment 04)

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the Core Study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Approximately 60 (±20%) eligible MCI/Prodromal or mild to moderate AD subjects will be 
randomized at approximately 35 sites in the United States (revised per Amendments 02 and 
04).  There will be no restriction to the number of subjects from either population.  
Subjects who do not meet all of the inclusion criteria in Section 9.3.1 or who meet any of the 
exclusion criteria in Section 9.3.2 will not be eligible to receive study drug during the Core 
Study.
Subjects who do not meet all of the inclusion criteria or who meet any of the 
exclusion criteria provided in Appendix 6 will not be eligible to enter the Extension Phase.
(revised per Amendment 07) 
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
Page 84 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 58 of 164
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia and also complies with the following: (revised per 
Amendment 01)
Required at Screening Visit 1:
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
Page 85 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 59 of 164
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
Page 86 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 60 of 164
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization  
20. Any active infection within the last 4 weeks before randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
investigator and the medical monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
Page 87 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 61 of 164
clinical immunodeficiency.  The discussion with the medical monitor should include a
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Page 88 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 62 of 164
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study. Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.

(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).  (revised per Amendment 04)
Page 89 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 63 of 164
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-up Visits 
will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug in the Core 
Study (see Section 9.1.2.3), and 4 and 12 weeks after the last dose of study drug in the 
Extension Phase (see Appendix 6). (revised per Amendments 04, 05, and 07)
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug during the Core Study include the 
following: (revised per Amendments 07)
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test but who 
has no clinical signs or symptoms of infection, will have study drug temporarily 
suspended for at least 2 weeks but no more than 4 weeks.  During this period of study 
drug suspension, lymphocyte subset counts and complete blood count (CBC) with 
differentials will continue to be tested weekly until CD4 (T helper cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) have all returned to greater than the population-adjusted 
LLN after which time study drug can be resumed.  Testing of lymphocyte subset counts 
and CBC with differentials is required weekly for 4 weeks following resumption of study 
drug administration.  Temporary suspension and rechallenge with study drug is only 
permitted once for any given subject.  If the lymphocytes and CD counts do not return to 
greater than the population-adjusted LLN within 4 weeks from the start of temporary 
suspension the subject will need to be permanently discontinued from study drug.  
(revised per Amendment 04)
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendments 02 
Page 90 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 64 of 164
and 04)  During the early stages of the Treatment Period, where visits are conducted 
weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already scheduled to be 
measured on a weekly basis and so additional visits or blood draws are not required.  
(revised per Amendment 02)  For these subjects, the decision as to whether the subject 
remains on study drug or is to be discontinued from study drug will be based upon 
clinical judgment and will take into account any clinical presentation in addition to the 
lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue, 
discontinue, or temporarily 
suspend study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts below 
discontinuation threshold and no clinical signs 
or symptoms of infection
Retest within 1 week along 
with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
temporarily suspend study 
drug for between 2 and 
4 weeks.  Continue weekly 
testing of lymphocyte subsets 
and CBC with differentials.  
Rechallenge with study drug 
allowed when CD4 (T helper 
cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) 
absolute counts all greater 
than population-adjusted 
LLN.  Temporary suspension 
and rechallenge permitted 
only once for each subject.
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold
Lymphocyte subset counts 
(and CBC with differentials) 
to be performed weekly until 
lymphocyte subset counts 
return to ≥ population-
adjusted LLN 
Decision will be based upon 
lymphocyte subset counts 
and clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  
(Table revised per Amendments 02 and 04)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
Page 91 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 65 of 164
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds, subjects with infections of moderate intensity will be 
discontinued from study drug (eg, subjects whose infections are not localized, or subjects 
who are systemically unwell, or who require systemic anti-infective drug treatment).   All 
subjects with infection who are discontinued from study drug will be followed for a 
period of 12 weeks or until the infection resolves/stabilizes or until the CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have returned to 
greater than population-adjusted LLN (whichever comes latest).
(revised per 
Amendments 02 and 04)
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts below 
discontinuation threshold
If confirmed with 
repeat testing within 
1 week, then 
temporarily suspend 
study drug as per 
instructions above.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts between 
population-adjusted LLN and 
discontinuation threshold 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts always >
population-adjusted LLN 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  
(Table revised per Amendments 02 and 04)
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
Page 92 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 66 of 164
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-up Visits 2, 4, 8, and 12 weeks after the last 
dose of study drug.  They will also undertake an UNS Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
be performed at approximately the time of the final Follow-up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the Treatment Period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
(revised per Amendment 04)
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
Safety-related criteria for discontinuation of study drug during the Extension Phase are 
provided in Appendix 6. (revised per Amendment 07)
9.4
Treatments
9.4.1
Treatments Administered
For the Core Study, the test drug is elenbecestat and the control drug is placebo. (revised per 
Amendments 07) All study drugs are to be administered orally, QD, with food.  
Treatments to be administered during the Core Study are 5, 15, and 50 mg elenbecestat or 
placebo before the implementation of Amendment 06, and 50 mg elenbecestat or placebo 
after the implementation of Amendment 06 as shown in Figure 1.  (revised per Amendments
Page 93 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 67 of 164
01, 05, 06, and 07)  Study treatment will begin on Day 1 (at the study site) following 
Randomization and will continue for approximately 78 weeks.  Please refer to Table 7 and 
Section 9.5.1.4.1 for specific information on drug administration on days when PK sampling 
is to be performed.
Treatments to be administered during the Extension Phase are described in Appendix 6. 
(revised per Amendment 07)
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the Treatment Period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
Elenbecestat (E2609) tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo 
tablets of identical appearance will also be available. Each subject will receive 2 tablets, 
which combined will make up the required doses of elenbecestat 5, 15, 50 mg, or placebo.  
The tablets will be supplied by the sponsor in labeled blister packs.  The product-release 
certificates for elenbecestat and placebo will be included in the clinical study report for this 
protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either elenbecestat or placebo, or both (see Section 
9.4.2.3 for labeling details).
9.4.2.1
Chemical Name and Formula of Elenbecestat (E2609)

Test drug code:  
E2609

Generic name:  
Elenbecestat 

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
Page 94 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 68 of 164
9.4.2.3
Labeling for Study Drug
Elenbecestat will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups are 
described in Section 9.4.1. (revised per Amendments 01 and 05)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, initial doses will be selected such that at steady state, they will result 
in 25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of 
PD effects.  (revised per Amendment 06)
In Study 007, the relative bioavailability of a tablet formulation of elenbecestat in the fed and 
the fasted states compared with the capsule formulation in the fasted state (used in 
Studies 001 and 002) was investigated.
It was found that when the tablet form of 
Page 95 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 69 of 164
elenbecestat (50 mg) was administered with food, the exposure (ie, AUC) of the parent drug 
elenbecestat was higher, with lower maximum observed concentrations and reduced 
exposure to the metabolites, compared with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in the Core 
Study should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% 
at steady state, respectively (Table 3).
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
Elenbecestat Tablet 
Daily Dose (mg) 
With Food
Plasma Elenbecestat 
% Reduction CSF 
BACE1 Activity
% Reduction 
CSF A(1-x)
Cmax,ss
(ng/mL)
Css,av
(ng/mL)
AUC(0-24h)ss
(ng·h/mL)
5 
6.2
3.3
80.3
16.2
33
15 
18.6
10
240.9
36.6
56
50 
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = beta-amyloid converting enzyme, CSF = cerebrospinal fluid, Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from 
healthy volunteers, has also been supported by modeling of data from subjects with an
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1 
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of elenbecestat effects 
in healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients.  (revised per Amendment 01)
The exposure of the highest dose in the Core Study (50 mg QD tablet administered with 
food) is less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on elenbecestat
decreased by 3.1% from baseline, whereas the placebo control showed an increase of 8.7%), 
but this decrease was less than that observed at doses of 200 mg (22.9% decrease) or 
400 mg (17.3% decrease).  No subject had infections or drug rash while receiving 
elenbecestat 100 mg QD or at lower doses in Study 002, whereas at 200 and 400 mg QD, 4 
subjects had symptomatic orolabial HSV1 relapses and 2 subjects at the highest dose had 
drug rash.  The highest dose for Study 202 of 50 mg QD (tablet administered with food in the 
Core Study) is therefore expected to have a similar or better safety profile compared with the 
100 mg QD capsule (administered fasted) in Study 002.  Specific exclusion criteria, blinded 
and unblinded safety monitoring procedures, and safety criteria for discontinuation from 
Page 96 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 70 of 164
study drug are included in this study in order to mitigate any immunology-related risk with 
elenbecestat, particularly in light of the progression from 14 days of dosing (Study 002) to 
18 months of dosing in this study.
Interim analyses of the elenbecestat plasma PK for all subjects and the elenbecestat CSF PK 
and PD profiles will be performed on baseline data and samples collected after at least 4 
weeks of treatment.  These interim analyses, as well as analyses of safety data, will be 
performed on an ongoing basis.  Refer Section 9.7.3 for more detail. The median and mean 
percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for 
each dose of elenbecestat and its 90% CI for the median will be derived.  In addition, 
exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the observed 
PK and PD data and will relate the average steady state plasma concentration of elenbecestat
to steady state CSF Aβ(1-x) percentage reduction from baseline after at least 4 weeks of 
dosing.  (revised per Amendments 01, 02, 03, 04, and 05)
Unblinded interim analyses have indicated elenbecestat 50 mg per day produced relatively 
high levels of CSF Aβ reduction (greater than 50%) with an acceptable safety profile.  As a 
result, elenbecestat 50 mg has been selected as the dose for Phase 3 development.  To gain a 
more comprehensive safety and tolerability profile of elenbecestat 50 mg, subjects 
randomized to elenbecestat 5 and 15 mg will be re-assigned to elenbecestat 50 mg for the 
remaining of the 18-month Treatment Period with the provision that they will have at least 
12 weeks of treatment remaining in the Randomization Phase.  (revised per Amendment 06)
9.4.5
Selection and Timing of Dose for Each Subject
Elenbecestat is administered orally, QD, with food in the Core Study.  Study treatment will 
begin on Day 1 following randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
Elenbecestat and placebo will be administered as tablets of identical appearance during the 
Core Study.  
During the Randomization Phase and Follow-up Phase in the Core Study, subjects,
caregivers/informants, and all clinical site personnel involved with the conduct and 
interpretation of the study, including investigators will be blinded to the treatment codes
(double-blind).  In order to make decisions about the remainder of the study as well as the 
full elenbecestat clinical development program, the sponsor will unblind safety, PK, and PD 
data on an ongoing basis and perform interim analyses of these data.  (revised per 
Amendment 03)
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Page 97 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 71 of 164
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.
The PK/PD interim analyses will take place throughout the study as per Amendment 03 and 
will be conducted by an independent PK/PD scientist at the sponsor.  Any additional changes 
to dose required for this study will be reflected in a further amendment to the protocol and 
the Statistical Analysis Plan will detail how data will be handled in the primary analysis. 
(revised per Amendments 02 and 04)
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs during the Core Study and Extension Phase are 
provided in Appendix 2. (revised per Amendment 07) Prohibited medications are presented 
in Listing 1 through Listing 5.  Medications that are permitted with restrictions are listed in
Listing 6 through Listing 8. (revised per Amendment 04)
The types of agents listed below are not permitted before randomization unless discontinued 
according to the specific timeframes as shown below; these types of agents are not permitted 
during the Core Study or Extension Phase until after the last treatment visit:  (revised per 
Amendments 04 and 07)

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines
Page 98 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 72 of 164

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization.  However,
during the Treatment Period of the study, short term (not more than 14 days) use of 
steroids up to the equivalent of prednisolone 40 mg QD is permitted after discussion with 
the medical monitor. Dosing with study drug should be suspended from the time steroid 
treatment is started. Complete blood count and lymphocyte subsets (for Core Study and 
first 12 months of Extension Phase only) should be determined before starting steroid 
treatment and continue to be monitored weekly. (revised per Amendment 08) Study drug 
may be resumed after discussion with the medical monitor when the following conditions 
are met: (1) treatment with steroids has been completed for at least 1 week; (2) absolute 
lymphocytes not <LLN; (revised per Amendments 07) (3) no lymphocyte subsets are 
below the discontinuation threshold (for Core Study only); (4) the investigator considers 
that the medical condition which required treatment with steroids has improved or 
resolved.  Weekly testing of lymphocyte subset counts (for Core Study only) and CBC 
with differentials (for Core Study and Extension Phase) is required for 4 weeks following
resumption of study drug administration.  (revised per Amendment 04)

(revised per Amendment 06)
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for any 
efficacy analyses.  (revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed.  Subjects who are on anticoagulants may have a variable dose but should have 
stable anticoagulation control for at least 4 weeks before randomization. They may be 
required to stop their anticoagulant medication prior to CSF collection and then restart 
this medication after the LP procedure, as per local guidelines.  (revised per 
Amendment 04)

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  (revised per Amendment 05)
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any 
other antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and
Page 99 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 73 of 164
clopidogrel (or any other antiplatelet drug which is not aspirin) in combination are also 
permitted but subjects who are on such a combination of antiplatelet drugs may be 
required to stop 1 or more of these antiplatelet drugs before the LP procedure and restart
after the LP as per local guidelines.   

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, are permitted.   
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
Clinical research associates will review treatment compliance during site visits and at the 
completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Page 100 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 74 of 164
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study 
drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator (or if regionally required, the head of the medical institution or the 
designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
Page 101 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 75 of 164
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6,
Table 7, and Table 14.  (revised per Amendment 07) A complete physical examination will 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, and skin, and a neurological examination (including the Brief Smell 
Identification Test [Sensonics Inc.]). 
(revised per Amendment 04).  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Significant findings at the Screening Visit will be recorded on the Medical History 
and Current Medical Conditions eCRF.  Changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
Page 102 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 76 of 164
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6, Table 7, and Table 14.  
(revised per Amendment 07) These assessments should be administered in the morning (or, if 
not possible, consistently at the same time of day) and should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  At the 
Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), 
CBB, ISLT (delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The 
CBB may be repeated multiple times if required for the subject to pass completion and 
integrity criteria.  At the Baseline Visit, the assessments are to be conducted in the following 
order:
MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT
(delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
Alzheimer's Disease Assessment Scale - cognitive subscale:  Discussed in Section 9.2.3.  
(revised per Amendment 05)
Clinical Dementia Rating:  The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
ISLT:  The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects will read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Page 103 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 77 of 164
CogState Brief Battery:  The CBB is a computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.

Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.

One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
Functional Assessment Questionnaire: The caregiver or informant provides performance 
ratings (from 0 to 3) on 10 complex activities of daily living performed within the preceding 
4 weeks.  Scores range from 0 (independent) to 30 (dependent).  (revised per Amendment 04)
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans
obtained at the times specified in Table 6, Table 7, and Table 14 according to standard 
quality control and normalization procedures for measurements of the whole brain and total 
ventricular volume.  (revised per Amendment 07) Measurements of the right and left 
hippocampal volumes will be based on a validated algorithm and conducted in the same 
laboratory.  Additional analysis of regions of interest and cortical thickness may also be 
performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
Page 104 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 78 of 164
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of elenbecestat.  
For subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of elenbecestat concentrations. (revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with elenbecestat.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food (in the Core Study) at the clinic after collection of the predose PK sample.  At Visit 
7 and Visit 18 (or at the ED Visit) the PK blood sample should be collected shortly before or 
shortly after completing the LP. (revised per Amendment 01)  Although the PK sampling 
procedures at the ED visit should follow those of Visit 18, in the event that study drug has 
already been discontinued before the ED visit, then no dosing will be conducted. However, a 
PK sample at trough (before LP) will be collected, followed by LP at approximately the same 
time as previous visits.  A 2nd PK blood sample will be collected as close as possible in time 
to the LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the 1st report of an SAE or severe unexpected AE 
and at its resolution.
Page 105 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 79 of 164
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal (Section 9.5.1.3.3).  The timing of the Baseline LP needs 
to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization 
timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  (revised per Amendment 04)  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 levels and activity.  (revised per 
Amendment 04)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses.  Aβ(1-x) in both CSF and plasma will be measured using a modified 
commercially available enzyme-linked immunosorbent assay (ELISA).  The pre- and 
postscreening analysis of CSF Aβ(1-42), Aβ(1-40), t-tau, and p-tau will be performed using 
commercially available ELISAs.  (revised per Amendment 04)  BACE1 levels will be 
measured using internally developed fluorescence resonance energy transfer and ELISA 
based assay(s).  Substrates of BACE1 inhibition may also be explored using Western blots or 
other amenable methodology if clinical observations warrant and if analytes can be reliably 
tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
For subjects who consented to CSF sample collection, CSF samples from the Baseline Visit 
will also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, 
Page 106 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 80 of 164
but not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, 
or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6, Table 7, and 
Table 14.  (revised per Amendment 07) 
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of elenbecestat. Details of which 
genotype/phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in elenbecestat exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
single–nucleotide polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of Core Study treatment (or at the Core Study ED Visit if the
subject has received study drug for at least 39 weeks).  (revised per Amendment 07) 
Longitudinal amyloid PET imaging will only be conducted on subjects with Screening PET 
scans performed for this study (ie, historical scans cannot be used for the longitudinal 
analyses) (Table 6).  (revised per Amendments 02 and 05)  PET scanning will be performed 
with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of elenbecestat.  
Page 107 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 81 of 164
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6, Table 7, and Table 14 will also be conducted. Additionally, during the 
Extension Phase, clinical assessment of suicidal thinking and behavior will be conducted 
only at visits that do not include administration of the C-SSRS; a positive suicidality 
assessment from the subject or the caregiver/informant on the clinical assessment of 
suicidality (ie, a “yes” response on the clinical assessment of suicidal thinking and behavior) 
will trigger the C-SSRS to be administered.  Peripheral blood mononuclear cells (PBMCs) 
will be collected for exploratory immunomodulatory and immune-based analyses at Baseline, 
during treatment, and posttreatment period of the Core Study and at Extension Phase 
Baseline (Visit 21), 6 months (Visit 26), 12 months (Visit 28), and 24 months (Visit 32).  
(revised per Amendments 07 and 08)  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is elenbecestat.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not necessary 
to report every sign or symptom as a separate AE if the overall disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, discontinuation of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
Page 108 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 82 of 164
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit during the Core Study (Visit 20, as shown in 
Table 7, for subjects who do not enter the Extension Phase) or the last Visit during the 
Extension Phase (Follow-up Week 12 Visit as shown in Table 14, for subjects who 
participate in the Extension Phase).  (revised per Amendment 07)  Subjects who fail 
screening primarily due to AE(s) must have the AE(s) leading to screen failure reported on 
the Screening Disposition eCRF.  SAEs will be collected for 3 months after the last dose of 
study drug, (ie, through to the final Follow-up visit [Visit 20 for subjects who do not enter 
the Extension Phase or Follow-up Week 12 Visit for subjects who participate in the 
Extension Phase]).  (revised per Amendments 04, 05, and 07)
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc 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.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADAS-cog14, MMSE, ISLT and CBB (see 
Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment Period, 
and if this cognitive decline is considered by the investigator to be excessive relative to the 
subject’s recent AD history, this finding should be reported as an AE.  
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis
Page 109 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 83 of 164

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS/clinical 
assessment of suicidality in all subjects and determine if any result constitutes an AE.  
Medical and scientific judgment should be exercised in deciding whether an isolated 
suicidality rating scale response should be classified as an AE (see Section 9.5.1.5.11 for a 
description of the C-SSRS and of the clinical assessment of suicidality).  (revised per 
Amendment 08)
The following AEs will require the collection of information sufficient to provide a detailed 
description of the event, treatment and outcome to the medical monitor for the study: any 
treatment-emergent significant laboratory abnormality; any seizures, herpes zoster infection, 
severe infection; any moderate to severe drug rash or any rash lasting more than 72 hours 
(regardless
of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); 
treatment-emergent depigmentation/hypopigmentation/vitiligo/loss of hair color; amyloid-
related imaging abnormalities (cerebral vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a new microhemorrhage); a “yes” answer to any suicidality
assessment on the C-SSRS or a positive suicidality assessment on the clinical assessment of 
suicidality (ie, a “yes” response on the clinical assessment of suicidal thinking and behavior).  
(revised per Amendment 08)  
All AEs must be followed through the final Follow-up Visit (Visit 20 for subjects who do not 
enter the Extension Phase or Follow-up Week 12 Visit for subjects who participate in the 
Extension Phase), or until resolution, whichever comes first.  (revised per Amendments 07
and 08) All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
(revised per Amendment 04)
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Page 110 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 84 of 164
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
Page 111 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 85 of 164
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6, Table 7, and Table 14 show 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 07)
See Section 9.3.3 for safety criteria for discontinuation from study drug-related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.  See Appendix 
6 for safety criteria for discontinuation from study drug related to absolute lymphocyte 
counts.
Page 112 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 86 of 164
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening, Baseline, and Visit 21 only)  (revised per Amendment 02
and 07)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte T and B cell subset analyses (see Table 5).  Regulatory T cells (revised per 
Amendment 04)
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HbsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc.)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triiodothyronine and free 
thyroxin) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (including but not limited to CD3, CD4, CD8, CD45, CD19, 
CD16, CD56, and CD14) and absolute lymphocyte counts will be measured in order to 
provide the lymphocyte subset data as shown in Table 5.  In addition, Regulatory T cells will 
be measured.  Current sponsor data supports the literature showing there is an age-related 
decline in lymphocyte subsets (see Appendix 5). These data have been used to revise the 
LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts 
to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively) (revised per 
Amendments 02 and 04).  
Page 113 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 87 of 164
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
(Table 5 revised per Amendment 04)
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6, Table 7, and Table 14 by a validated method. (revised per 
Amendment 07) Measurements of sitting BP and heart rate will be obtained.  All BP 
measurements should be performed on the same arm, preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7 and Table 14.  (revised per Amendment 07) 
These examinations will include the cardiovascular system, respiratory system, and 
neurological system.  Health status will be evaluated by brief evaluation of the eyes, ears, 
nose, throat, and other physical conditions of note.  The subject must be queried regarding 
changes in physical status since the last examination.  A urogenital examination will only be 
required in the presence of clinical symptoms related to this region.  Documentation of the 
physical examination will be included in the source documentation at the site.  Only changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6, Table 7, and Table 14.  
(revised per Amendment 07) During the Core Study, 12-lead standard ECGs will be recorded 
Page 114 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 88 of 164
in triplicate (1 minute apart) after subjects have been resting in the supine position for at least 
5 minutes. During the Extension Phase, a single 12-lead ECG will be recorded after subjects 
have been resting in the supine position for at least 5 minutes.  If the QTcF is greater than 
450 msec on the first single 12-lead ECG, 2 additional 12-lead ECGs will be performed 
1 minute apart and the mean of the 3 QTcF values will be calculated. (revised per 
Amendment 07)
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6, Table 7, and 
Table 14. (revised per Amendment 07) Additional safety MRI scans can be performed at 
UNS Visits if clinically necessary.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2 Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, 18, 20, 32, and 38.  (revised per 
Amendments 04, 07, and 08) In the event of an UNS Visit, the investigator in consultation 
with the sponsor will determine whether or not a safety MRI should be conducted.  If an ED
Visit takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.  If subjects have non-MRI compatible devices fitted during treatment, then a 
computed tomography scan may be utilized to assess safety, if deemed appropriate by the 
investigator. (revised per Amendment 08)
Page 115 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 89 of 164
At any time during the Treatment Period, subjects will be discontinued from study drug if 
they develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an 
area of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must 
be reported as study specific AEs (or AEs of special interest).  These subjects will undergo 
an ED Visit within 7 days after study drug discontinuation as well as 4 Follow-up Visits at 2, 
4, 8 and 12 weeks after the last dose of Core Study treatment or 2 Follow-up Visits at 4 and 
12 weeks after the last dose of Extension Phase treatment.  (revised per Amendments 04 and 
07) Subjects will also undertake an UNS Visit (with MRI) at approximately 30 days after the 
visit at which such MRI features were first identified.  Additional visits may be arranged if 
clinically indicated in the opinion of the investigator, and may occur later than 12 weeks after 
the final dose of study drug.
9.5.1.5.8
DERMATOLOGIC ASSESSMENT
During the Core Study, centralized skin assessments, using standardized photography, will be 
performed by a reviewing dermatologist at the times shown in Table 6 and Table 7.  During 
the Extension Phase, all dermatologic assessments will be performed by the investigator at 
the times shown in Table 14.  (revised per Amendment 07) All assessments will specifically 
include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGIC EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6, Table 7, and Table 14.  (revised 
per Amendment 07) Details of these examinations will be captured in an eCRF.  The 
neurological examinations will monitor for new symptoms and signs which will then alert the 
investigator to consider new CNS pathology (especially slowly-evolving neurological 
conditions that may not lead to prominent symptoms).  Examples of neurological signs that 
may indicate new CNS pathology that may need further investigation include (but not limited 
to) visual disturbance, dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, 
paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or 
cognitive decline in excess of expectations based on the subject’s recent history.  In such a 
situation, the investigator should consider (but not limited to) demyelination in the 
differential diagnoses, and should discuss with the sponsor’s medical monitor further 
Page 116 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 90 of 164
investigations or treatment, which will be decided case by case.  Neurological examinations 
will also include the assessment of cranial nerve function, especially the olfactory nerve; the 
Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits to 
objectively test olfaction.  Treatment-emergent abnormal neurological findings should be 
reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening and Visit 21, females of childbearing potential will have a serum pregnancy 
test.  At Baseline and during the Treatment Period, urine samples will be obtained from 
females of childbearing potential for pregnancy tests (see Table 7 and Table 14). (revised per 
Amendment 07)
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6, Table 7, and Table 14.  During the Extension Phase, a more 
general clinical assessment by the investigator, involving both the subject and the 
caregiver/informant, will be conducted at visits that do not include administration of the C-
SSRS. A positive suicidality assessment from the subject or the caregiver/informant on the 
clinical assessment of suicidality (ie, a “yes” response on the clinical assessment of suicidal 
thinking and behavior) will trigger the C-SSRS to be administered.  A “yes” answer to Type 
4 or 5 suicidal ideation or a “yes” response to any suicidal behavior queries will trigger 
additional psychiatric evaluations by a psychiatrist to determine how the subject is to be 
managed clinically.  All sites are required to identify a psychiatrist for referral purposes.  The 
subject’s ability to continue to participate in the study will be determined by the investigator 
in consultation with the medical monitor. (revised per Amendments 07 and 08)
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
Page 117 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 91 of 164
9.5.2
Schedule of Procedures/Assessments
The Schedule of Procedures/Assessment is described in this section for the Core Study only.  
The Schedule of Procedures/Assessment for the Extension Phase is provided in Appendix 6, 
Table 14. (revised per Amendment 07)
9.5.2.1
Schedule of Procedures/Assessments
Table 6
presents the Schedule of Procedures/Assessments for the Core Study 
Prerandomization Phase.  Screening assessments will be organized into 4 tiers (see below and
Figure 2). Table 7 presents the Schedule of Procedures/Assessments for the Core Study 
Randomization Phase.
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary)a
X
X
Demographics
X (Tier 1)
Medical historyb
X (Tier 1)
Prior/concomitant medicationsc
X (Tier 1)
X
Vital signs including weightd
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTe
X (Tier 1)
X
MMSEe
X (Tier 1)
X
CDRe
X (Tier 1)
X
FAQe
X (Tier 1)
X
ADAS-cog14e
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGf
X (Tier 2)
X
Blood and urine for clinical laboratory testsg
X (Tier 2)
X
Blood for lymphocyte subset analysesh
X (Tier 2)
X
Blood for Ig analysesi
X (Tier 2)
X
Blood for viral screenj
X (Tier 2)
Blood for thyroid function testsk
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIl
X (Tier 3)
Amyloid PET scanm
X (Tier 4)
Page 118 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 92 of 164
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagea
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
(Table revised per Amendments 02 and 04)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = cytomegalovirus, 
CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = 
Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), HBsAg = hepatitis B surface 
antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial herpes), HSV2 = herpes simplex 
virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, ISLT = International Shopping List 
Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental State Examination, MRI = magnetic 
resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetics, PET = 
positron emission tomography, PT = prothrombin time, PTT = partial thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of all 
Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities. 
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and exclusion 
criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
Subjects who initially consented to CSF collection and provided a baseline CSF sample but did not provide a 
postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample collection 
even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
For those subjects who do consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or 
at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be encouraged 
to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed 
between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each individual subject.  If the LP and 
cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been completed 
and the subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used for PK and PD 
assessments.  A CSF sample will also be stored for testing in the event that the subject develops TEAEs that warrant 
further investigation (eg, treatment-emergent infection).  (revised per Amendments 01, 02, and 04)
Page 119 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 93 of 164
b:
To include:  mild cognitive impairment and AD history; history of TB, vaccination history against and infections due to 
varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include:  onset, duration, relapse frequency, severity, and 
treatments.  For any active infection within the last 4 weeks before randomization, the timing of randomization can be 
extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory 
tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
c:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
d:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
e:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should 
be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At the 
Screening Visit, the recommended order of assessments is:  MMSE, ISLT (immediate recall), CBB, ISLT (delayed 
recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria. At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
f:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
g:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
h:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD19 (B cells), CD16/CD56 (natural killer cells) and CD14 (macrophages).  
Regulatory T cells will also be measured.  Viability staining may also be employed.  Whenever unscheduled 
lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a CBC with 
differentials, must also be repeated.   (revised per Amendments 02 and 04)
i:
Igs to be analyzed include IgG, IgA and IgM.
j:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
k:
Thyroid function tests include thyroid stimulating hormone, free triiodothyronine, and free thyroxin.
l:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.  MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
m:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an agent 
under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining eligibility 
for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the previous 12 
months and provided that the scan and result are considered acceptable by the central PET reading group.   (revised per 
Amendment 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops TEAEs that warrant further investigation 
(eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior 
exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurologic examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.  The Brief Smell 
Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of the neurological 
examination. (revised per Amendment 04)
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
Page 120 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 94 of 164
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion 
criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological 
assessment via photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and 
urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (lymphocyte 
subset analyses)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (Igs)m
X
X
X
X
X
X
X
X
X
X
X
Blood samples (isolation of 
PBMCs)
X
X
X
Urine pregnancy test (females 
of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample (storage for 
immune status)o
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14p
X
X
X
X
X
X
X
X
X
Page 121 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 95 of 164
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and 
exploratory biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, MMSE 
= Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled, W2 = new Week 2 Follow-up Visit, W8 = new Week 8 Follow-up Visit.  (revised per Amendment 04)
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-up Visits 
will be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (Visit W2, 19, W8, and Visit 20, respectively).  (revised per Amendments 04 and 05)  
Page 122 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 96 of 164
Footnotes for Table 7
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 4 posttreatment Follow-up Visits; 2, 4, 8, 
and 12 weeks after the last dose of study drug (Visits W2, 19, W8, and 20, respectively).  If clinically indicated, more frequent safety assessments can be made as UNS 
assessments or visits during the posttreatment Follow-up Period.  (revised per Amendment 04)
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at the previous Follow-up Visit.  (revised per Amendments 02 and 04)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history. The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of 
the neurologic examination. (revised per Amendment 04)
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [NK cells] and CD14 [macrophages]) and absolute lymphocytes.  Regulatory T cells will also be measured. Viability staining may also be employed.  Whenever 
unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be 
performed along with assessment of AEs. (revised per Amendments 02 and 04)
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops a TEAE that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective 
agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors.  
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within the 
7 days before Visits 14, 16, 18, and 20.  In the event of an UNS Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI should be 
Page 123 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 97 of 164
Footnotes for Table 7
conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will be collected in all 
subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14, and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  Postrandomization CSF sample collection is scheduled at Visit 7 (or later postrandomization timepoint) and Visit 18/ED.  
If a postrandomization CSF sample is collected later than Visit 7, time-matched plasma PK samples are also required (see Footnote t).  All visits at which CSF samples are 
scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. The timing of the Baseline LP needs to be 
scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity 
drip collection method must be used.  If the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been completed
and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical observation.  The 
CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already stopped study drug, then 
no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample 
collection even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects. (revised per Amendments 01, 02, and 04)  
w:
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 124 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 98 of 164
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the Core Study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.5.2, and Figure 2.  (revised per amendment 07)
See Section 9.5 for a full description of the procedures and assessments to be performed 
during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the Core Study.  Additional samples may be taken at 
the discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety. (revised per amendment 07)
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points × volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline Periods
Treatment and 
Follow-up
Periods
Blood
Chemistry
12
2 × 2 mL
10 × 2 mL
24 mL
Hematology
20
2 × 5 mL
18 × 5 mL
100 mL
Lymphocyte subset analysesa
20
2 × 4 mL
18 × 4 mL
80 mL
PBMC
4
1 × 16 mL
3 × 16 mL
64 mL
IgA, IgM, IgG
10
2 × 2 mL
8 × 2 mL
20 mL
PT, PTT for INR
2
2 × 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triiodothyronine and free thyroxin)
1
1 × 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 × 4 mL
None
4 mL
Viral characterization
1
1 × 4 mL
None
4 mL
Vitamin B12
1
1 × 2 mL
None
2 mL
Serum pregnancy test
1
1 × 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 × 3 mL
None
3 mL
Sample for immune status
8
1 × 4 mL
7 × 4 mL
32 mL
PD sample
9
1 × 4 mL
8 × 4 mL
36 mL
PK analysis
7
1 × 3 mL
6 × 6 mL
39 mL
Pharmacogenetic sample
1
1 × 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
342 mL
422 mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 × 12 mL
2 × 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 125 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 99 of 164
a:
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, 
a CBC with differentials must also be performed. Therefore, for each unscheduled or repeat test, an additional 9 mL 
will be collected (5 mL for hematology and 4 mL for lymphocyte subset analyses) 
(Table 8 revised per Amendment 04)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with elenbecestat, in addition to mitigating clinical risk in 
the progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.5.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the final Follow-up Visit (Visit 20 for subjects who do not enter 
the Extension Phase or Follow-up Week 12 Visit for subjects who participate in the 
Extension Phase).  (revised per Amendments 04, 05, 07, and 08)  However, any SAEs 
volunteered by subjects after this time point must be reported according to standard 
procedures.  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.
Page 126 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 100 of 164
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
Page 127 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 101 of 164
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
Page 128 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 102 of 164
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-up Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study 
drug in the Core Study (Visits W2, 19, W8, and Visit 20, respectively) or 4 and 12 weeks 
after the last dose of study drug in the Extension Phase (see Section 9.1.2.3). (revised per 
Amendments 04, 07, and 08) See Table 7 and Table 14 for full details of the assessments to 
be performed at these visits.  (revised per Amendments 05 and 07) Subjects who discontinue 
study drug early (as opposed to subjects whose dosing with study drug is temporarily 
suspended under medical monitor guidance) will not be permitted to restart study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal 
of consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary 
Page 129 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 103 of 164
reason, the subject may indicate 1 or more secondary reason(s) for withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Abuse or Diversion of Study Drug eCRF. (revised per 
Amendment 04)
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Page 130 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 104 of 164
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
9.7.1
Statistical and Analytical Plans
The statistical analyses of Core Study data are described in the following sections. Statistical 
analyses of Extension Phase data are provided in Appendix 6. (revised per Amendment 07) 
Analyses will be performed based on treatment group, which will be defined in the statistical 
analysis plan (SAP). Additional analyses related to dose re-assignment will be performed for 
subjects who will be switched from elenbecestat 5 or 15 mg to elenbecestat 50 mg.  Further 
details will be provided in the SAP, which will be finalized before database lock. (revised 
per Amendment 06)
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

Safety and tolerability, which include incidence of TEAEs and SAEs, laboratory 
parameters, vital signs, and ECG parameters (revised per Amendment 05)
9.7.1.1.2
SECONDARY ENDPOINTS
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after from 4 weeks and 
up to 18 months of treatment 
Page 131 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 105 of 164

The population PK parameters of elenbecestat in CSF and plasma, including the effect of 
intrinsic and extrinsic factors (including NAT2 phenotype) (revised per Amendment 07)
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01, 02, 04, and 05)  
Change from baseline in:  

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) after at least 
4 weeks and at 18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment   

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and 
during posttreatment follow-up 

CSF amyloid and CSF BACE1 measurements after 4 weeks and 18 months of treatment
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months of treatment as measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain 
amyloid levels as measured

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose exploratory efficacy 
measurement.  (revised per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable elenbecestat
plasma concentration accompanied by a documented dosing history.
(revised per 
Amendment 07)

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Page 132 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 106 of 164
Disposition eCRF.  The number of randomized subjects enrolled at each site will be 
summarized by treatment group.  The primary reasons for screen failures (did not meet 
inclusion or met exclusion criteria, AE, lost to follow-up, withdrawal of consent, and other) 
will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized by treatment group using descriptive statistics.  Continuous demographic and 
baseline variables include age, MMSE and FAQ; categorical variables include sex, age group 
(≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014 or higher).  
(revised per Amendment 04) The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the Safety Analysis Set by treatment group, 
Anatomical Therapeutic Chemical class, and WHO DD preferred term.  Prior medications 
will be defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
Page 133 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 107 of 164
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the date of the last dose.  All medications will be 
presented in subject data listings.
Medications taken within the 12-week Follow-up Period will also be recorded.
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05)
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
There is no primary efficacy endpoint.  (revised per Amendment 05)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 
18 months.  Data from early discontinuations will also be included. 
(revised per 
Amendment 05)
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01, 02, 04, and 05)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months.  Data from early discontinuations will also be 
included. (revised per Amendment 04)

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 
18 months of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 
18 months of treatment, and during posttreatment follow-up 

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and 
up to 18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by 
vMRI

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12, and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid 
levels
Page 134 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 108 of 164
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for elenbecestat concentration listings and for summaries 
of elenbecestat concentrations in plasma and CSF by dose and day.  Elenbecestat metabolite 
PK data may also be listed and summarized. (revised per Amendment 04)
A population PK approach will be used to characterize the plasma PK of elenbecestat.  For 
this approach, plasma PK data from this study will be pooled with relevant data from Phase 1 
studies.  As appropriate, the effect of covariates on the PK of elenbecestat will be evaluated.  
The PK model will be parameterized for oral clearance (CL/F) and apparent volume of 
distribution (Vz/F) for elenbecestat. Derived exposure parameters such as steady state AUC 
and average concentration (Cavg) of elenbecestat and other derived parameters will be 
calculated from the model using the individual estimates parameterized for oral clearance and 
dosing history.  (revised per Amendment 04)
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  The percentage change from baseline in CSF 
Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months of treatment will be analyzed and presented 
graphically. (revised per Amendment 05)  Baseline levels and changes in t-tau and p-tau will 
be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  (revised 
per Amendment 04)  
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Page 135 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 109 of 164
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
elenbecestat dose, plasma, and CSF exposure will be initially explored graphically and any 
emergent relationship will be explored through population PK/PD modeling. The PK/PD 
relationship between plasma PK parameters with other biomarkers may also be explored 
using similar methods.  (revised per Amendment 04)  
The relationship between plasma and CSF exposure to elenbecestat and the clinical efficacy 
scales (eg, MMSE, CDR) will be explored graphically.  Additionally, the relationship 
between plasma exposures of elenbecestat and select lymphocyte parameters will be explored 
graphically, and any emergent relationship will be explored using population-based modeling 
methods.  (revised per Amendment 04)  
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, vital sign measurements, and cognitive decline assessment such as CBB will be 
summarized by treatment group using descriptive statistics.  (revised per Amendment 05)
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The cumulative number and percent of subjects will be presented by 
treatment group.  Duration of exposure will be summarized using descriptive statistics as 
continuous variable as well as categorical variable in 3-month intervals and the number and 
percent of subjects will be presented by treatment group.
Page 136 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 110 of 164
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  A subject data listing of all AEs 
leading to death will be provided.
Page 137 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 111 of 164
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets measured (including but not limited to CD4 [T helper cells], CD8 
[cytotoxic T cells], CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 
[macrophages] and regulatory T cells) will be summarized in the same manner as other 
laboratory parameters.  Mean lymphocyte subsets and the mean change from baseline in 
lymphocyte subsets will also be displayed graphically over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
Page 138 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 112 of 164
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the Treatment Period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include CBB (Section 9.7.1.6).  (revised per Amendment 05)
Page 139 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 113 of 164
9.7.2
Determination of Sample Size
A total of 15 subjects per dose group is deemed sufficient to derive adequate safety and 
PK/PD data to aid in the selection of appropriate doses and the design of the Phase 3 studies 
that may be planned subsequently.  (revised per Amendment 05)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full elenbecestat
clinical development program, the sponsor will unblind safety, PK, and PD data on an 
ongoing basis and perform interim analyses of these data.  Investigators, other clinical site 
staff, subjects, caregivers/informants, and study team will remain blinded to study treatment.  
(revised per Amendments 03 and 05)
An interim safety analysis will also be conducted when all subjects have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)  
9.7.4
Other Statistical/Analytical Issues
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
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.
Page 140 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 114 of 164
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test. 
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Page 141 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 115 of 164
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology.
2007;68:1588-95.
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 142 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 116 of 164
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association 
workgroups 
on 
diagnostic 
guidelines 
for 
Alzheimer's 
disease.
Alzheimers Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 143 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 117 of 164
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 144 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 118 of 164
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 145 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 119 of 164
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 146 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 120 of 164
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (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 designated contractor).
Page 147 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 121 of 164
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 CTA 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 CTA 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 CTA 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.
Page 148 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 122 of 164
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.
Page 149 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 123 of 164
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN = 15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN = 17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN = 10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN = 379 103/µL)
<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) 
2 - 59 years (ULN = 5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 - 69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 - 79 years (LLN-ULN)
<3.5 g/dL – 3 g/dL
79 - 89 years (LLN-ULN)
<3.5 g/dL – 3 g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 - 19 years
>101 – 3.0101
19 - 61 years
ULN=107
61 - 71 years
ULN=112
71 - 150 years
ULN=108
Male
18 - 19 years
>127 – 3.0127
19 - 61 years
ULN=102
61 - 71 years
ULN=103
71 - 150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Female:
>3.0 – 5.032
Female:
>5.0 – 20.032
Female:
>20.032
Page 150 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 124 of 164
Grade 1
Grade 2
Grade 3
Grade 4
Male:
>44 – 3.0 x 44
Male
>3.0 – 5.044
Male:
>5.0 – 20.044
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 - 19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 - 150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 151 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 125 of 164
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 152 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 126 of 164
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1 through Listing 5.  Medications permitted with 
restrictions are listed in Listing 6 through Listing 8.  (revised per Amendment 04) These may 
not be all-inclusive listings.  Please contact the medical monitor(s) if the investigators have 
any questions or concerns regarding any medication not listed that your subjects may be 
taking before enrollment or start during the course of the E2609-G000-202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 153 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 127 of 164
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Biaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 154 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 128 of 164
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 155 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 129 of 164
Listing 2 Prohibited Medications Within 5 Half-lives or 60 days, Whichever is Longer, 
Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa,b and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
b:
During the Treatment Period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the medical monitor. Dosing with 
study drug should be suspended from the time steroid treatment is started. Complete blood count and 
lymphocyte subsets (for Core Study and the first 12 months of Extension Phase only) should be determined 
before starting steroid treatment and continue to be monitored weekly. (revised per Amendment 08) Study 
drug may be resumed after discussion with the medical monitor when the following conditions are met: (1) 
treatment with steroids has been completed for at least 1 week; (2) absolute lymphocytes not <LLN; (3) no 
lymphocyte subsets are below the discontinuation threshold (for Core Study only); (4) the investigator 
considers that the medical condition which required treatment with steroids has improved or resolved.  
Weekly testing of lymphocyte subset counts (for Core Study only) and CBC with differentials is required 
for 4 weeks following resumption of study drug administration.  (revised per Amendment 04)
Page 156 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 130 of 164
Listing 3 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 157 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 131 of 164
Listing 4 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 158 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 132 of 164
Listing 5 Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 159 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 133 of 164
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Final Follow-Up Visit 
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 160 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 134 of 164
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, 
Oramorph SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
PRN = Pro re nata
Page 161 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 135 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 162 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 136 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, Depakote ER, Divalproex Sodium, Stavzor, 
Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan 
Page 163 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 137 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 164 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 138 of 164
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), pharmacogenomic (PGx), and other biomarker analysis.  These
samples may be used for discovery and validation to identify biomarkers that may be used 
for exploratory evaluation of response or safety-related outcomes as well as for use in 
diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events (AEs) related to study drug, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or non-coding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug PK or therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
Page 165 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 139 of 164
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH] E15 
guidelines) in order to maintain subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject indentification [ID]) and replacing with another 
code such that the subject can be re-identified by use of 2 code keys.  The code keys are 
usually held by different parties.  The key linking the sample ID to the subject number will 
be maintained separately from the sample.  At this point, the samples will be double-coded,
the first code being the subject number.  Laboratory personnel performing genetic analysis 
will not have access to the “key.”  Clinical data collected as part of the clinical trial will be 
cleaned of subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

Contract research organizations (CROs) retained by the sponsor

Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs) that 
have responsibility for this research study

National regulatory authorities or equivalent government agencies
Page 166 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 140 of 164
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 167 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 141 of 164
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Page 168 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 142 of 164
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Relaxed
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 169 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 143 of 164
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 170 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 144 of 164
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These lower limits of normal (LLN) for the 
various lymphocyte subsets are currently being used by the central laboratory for Eisai Study 
E2609-G000-202 to determine eligibility of screened subjects and as part of safety 
assessments during post-randomization visits. The eligibility criterion excludes subjects with 
absolute counts of T and B cell markers (CD4, CD8, and CD19 respectively) less than the 
reference range LLN at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance (3) may 
not be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (Clinical and Laboratory 
Standards Institute’s, 2010(4)) recommends examining data to determine if >10% of subjects 
are outliers (ie, more than 10% <LLN), and if so, to initiate development of subgroup-
appropriate intervals by analyzing data from the literature or internal studies representing the 
reference population [a minimum of 120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with mild cognitive impairment (MCI) due to Alzheimer’s 
disease (AD) or with mild to moderate dementia due to AD.  Lymphocyte subset data from a 
Page 171 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 145 of 164
data cut of 93 screened subjects was analyzed and showed that both CD8 and CD4 had 
greater than 10% of the subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 
cells/mm3, respectively); CD19 had approximately 10% of the subjects with results <LLN 
(9.7%, <80 cells/mm3). 
To 
further 
determine 
if 
the 
outlier 
data 
observations 
from 
the 
ongoing 
Study E2609-G000-202 were associated with disease status or age, lymphocyte subset data 
from additional Eisai studies that included healthy elderly subjects or patients diagnosed with 
MCI or mild/moderate AD were examined. The individuals from all 3 studies included the 
same 50-to 85-year-old age range as the current E2609-G000-202 study. 
The studies 
evaluated include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) 
Lymphocyte subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot 
study in AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the
CD8 absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute 
counts below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of 
reference LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference 
values of LLN for CD4, CD8, and CD19 subsets are not a disease-associated observation but 
are related to the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life.
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1) 
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)
Page 172 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 146 of 164
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and 
Table 12), and a 10% cut value is applied to each of the 3 CD markers of interest the 
following age-adjusted LLN values are generated: 
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
Page 173 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 147 of 164
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 174 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 148 of 164
Appendix 6
Extension Phase 
(revised per Amendments 07 and 08)
PRIMARY OBJECTIVE

To assess the long-term safety and tolerability of daily dosing with elenbecestat 50 mg in 
mild cognitive impairment (MCI)/Prodromal subjects and in subjects with mild to 
moderate dementia due to Alzheimer's disease (AD)
SECONDARY OBJECTIVES

To explore the long-term effects of elenbecestat on clinical status by assessment of: 
a.
The Mini-Mental State Examination (MMSE)
b. The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the long-term effects of elenbecestat on:
a.
Volumetric magnetic resonance imaging (vMRI) including, but not limited to,
total hippocampal volume, left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 24 and 48 months of treatment in the 
Extension Phase.
b. Plasma amyloid at 12, 24, 36, and 48 months of treatment in the Extension Phase
ELIGIBILITY CRITERIA
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.
Inclusion:
1. Subjects who complete the 18-month treatment and the 12-week Follow-up Period 
(Visit 20) in the Core Study and whose Visit 20 falls within a 4-week window from the 
start of the Extension Phase (Visit 21).  Permission must be obtained from the medical 
monitor if Visit 21 is to occur more than 4 weeks from Visit 20.
2. Subjects must continue to have an identified caregiver or informant who is willing and 
able to provide follow-up information on the subject throughout the course of the 
Extension Phase. 
Exclusion:
1. Subjects who discontinue study drug prematurely during the Core Study are not eligible 
to participate in the Extension Phase.
Page 175 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 149 of 164
2. Subjects with any active infection within 4 weeks of Visit 21 
3. Subjects with absolute lymphocyte count below the Lower Limit of Normal (LLN) within 
10 days of Visit 21
4. Subjects who develop the following conditions from the time of screening for the Core 
Study to the start of the Extension Phase: 
a.
Hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7.  Subjects with 
Gilbert’s syndrome need not be excluded on the basis of an elevated bilirubin, 
provided that they have no other signs or symptoms suggestive of hepatic 
impairment
b. Any contraindications to magnetic resonance imaging (MRI) scanning, including 
cardiac pacemaker/defibrillator or ferromagnetic metal implants (eg, in skull; 
cardiac devices other than those approved as safe for use in MRI scanners)  
c.
Severe visual or hearing impairment that would prevent the subject from 
performing psychometric tests accurately
d. Immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
e.
Chronic viral hepatitis
f.
Tuberculosis (TB)
g. Ophthalmic shingles
h. Ocular herpes simplex virus (HSV) infection
i.
Any chronic inflammatory disease that is not adequately controlled or that 
requires systemic or ocular immunosuppressive or immunomodulatory therapy.  
Subjects with:  

Seasonal or perennial allergic rhinitis, asthma or chronic obstructive 
pulmonary disease where the condition is considered to be stable and 
adequately controlled by inhaled steroids need not be excluded  

Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy 
and not on systemic immunosuppressive therapy need not be excluded  

Cutaneous manifestations of immunological disease that do not require 
systemic immunosuppressive therapy or systemic immunomodulatory 
therapy need not be excluded (topical steroid treatment is permitted)
j.
Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the 
skin, or localized prostate cancer that did not require systemic therapy; these do 
not exclude the subject from the Extension Phase).
5. Subjects with prolonged QTcF interval at Visit 20 or Visit 21. Subjects with a single 
12-lead ECG QTcF >450 msec should have 2 additional ECGs performed at least 
Page 176 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 150 of 164
1 minute apart and the mean QTcF from the triplicate ECGs should be calculated. 
Subjects with a mean QTcF value >450 msec are not eligible to enter the Extension 
Phase.
6. Subjects with significant pathological findings on brain MRI including but not limited to: 
an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of 
cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective 
lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular 
territory, severe small vessel, or white matter disease; space occupying lesions; or brain 
tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 
1 cm at their greatest diameter need not be exclusionary)
7. Subjects who have a “yes” answer to the Columbia Suicide Severity Rating Scale 
(C-SSRS) suicidal ideation questions 4 or 5 at Visit 20 or Visit 21 or any suicidal 
behavior during the study prior to the start of the Extension  Phase
8. Female subjects of childbearing potential who meet any of the follow criteria:
a.
Do not agree to use a highly effective method of contraception (eg, total 
abstinence, an intrauterine device, a double-barrier method [such as condom plus 
diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or 
have a vasectomized partner with confirmed azoospermia) throughout the entire 
study treatment period and for 28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexually active during the study treatment period 
or for 28 days after study drug discontinuation
c.
Who do not agree to use the same contraceptive during the study treatment period 
or for 28 days after study drug discontinuation
9. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Visit 20 or 
Visit 21  
10. Subjects with medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that are not stably controlled, or which, in the opinion of the investigator(s), could affect 
the subject’s safety or interfere with the study assessments
11. Any other clinically significant abnormal findings in vital signs, ECGs and laboratory 
tests that would, in the investigator’s opinion, affect the subject’s safety or interfere with 
study assessments during the Extension Phase
STUDY DESIGN AND PLAN
The Extension Phase allows eligible subjects to receive elenbecestat 50 mg for up to 48 
months (4 years). 
Page 177 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 151 of 164
Subjects who are enrolled in the Core Study will have the option to participate in the 
Extension Phase provided that they complete the Core Study (which includes 18 months of 
double-blind treatment and 12 weeks of Follow-up Period) and satisfy the entry criteria for 
the Extension Phase.  Subjects who discontinue from study drug during the Core Study are
not eligible to participate in the Extension Phase.  
Eligible subjects who choose to participate in the Extension Phase may enter the Extension 
Phase immediately following the completion of Visit 20 (ie, Visit 21 procedures may be 
completed on the same day as Visit 20).  Subjects who are eligible to participate in the 
Extension Phase but who do not transition to the Extension Phase on the day of Visit 20 may 
enter the Extension Phase any time within 4 weeks of Visit 20.  The medical monitor must be 
contacted if Visit 21 is to occur more than 4 weeks after Visit 20.  For all subjects, 
assessments performed at Visit 20 may serve as baseline values for the Extension Phase (ie, 
results of assessments conducted at Visit 21) with exceptions of laboratory assessments and 
vital signs, which must be repeated if Visit 21 occurs more than 10 days from Visit 20.   
During the Extension Phase, subjects will receive open-label elenbecestat 50 mg per day for 
up to 48 months.  Subjects with pending INR and serum pregnancy test results (females 
subjects of childbearing potential only) but who are otherwise qualified may begin Extension 
Phase dosing at Visit 21; however, these subjects must discontinue study drug treatment 
immediately if either test result meet the exclusion criteria.
Safety assessments will be performed as described in Table 14.  Subjects may discontinue 
from study drug for any reason.  Subjects who complete 48 months of the Extension Phase 
treatment or who discontinue the study drug must comply with the Early Discontinuation 
(ED) Visit (within 7 days after the last dose of study drug) and the Follow-up Visits (Weeks 
4 and 12 after the last dose of study drug).
The study will end when the last visit for the last subject has completed the Extension Phase.
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason. Subjects who discontinue study drug 
prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study 
drug.  Subjects who discontinue from treatment during the Extension Phase will have 
2 posttreatment Follow-up Visits at 4 and 12 weeks after the last dose of study drug. 
Page 178 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 152 of 164
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug should be collected on the ED from study drug electronic 
case report form (eCRF) page (see Protocol Section 9.5.5). In addition, the date of last dose 
of study drug will be recorded on the Study Drug Dosing eCRF page. 
Safety-related criteria for discontinuation of study drug include the following:  
1. Absolute lymphocyte count will be monitored during the study. Should a subject develop 
lymphocytopenia (less than 800/mm3 or LLN, whichever is higher), a confirmation test 
should occur as soon as possible but no later than within 5 days with a repeat test of 
absolute lymphocytes. If confirmed, study drug administration should be interrupted for 
a minimum period of 2 weeks. Restart of study drug may take place only when absolute 
lymphocyte count returns to greater than LLN. Absolute lymphocyte count will be 
measured 4 weeks after restart of study drug. Subsequent measurements of absolute 
lymphocyte counts will follow the schedule of assessments and any results showing a 
Grade 2 or greater lymphocytopenia (less than 800/mm3) should be handled as above. If 
a 2nd occurrence of Grade 2 or greater lymphocytopenia (less than 800/mm3), that is 
confirmed on repeat testing, occurs within 6 months, then the subject should be 
discontinued permanently from the study drug.
2. A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (with the exception of oral or genital herpes as 
described in the next paragraph), will be discontinued from study drug and a 
dermatologic consult will be requested regardless of whether the rash is considered 
drug-related or due to other causes. For cases where the investigator suspects a drug 
rash, regardless of severity, the subject will be discontinued from study drug, a 
dermatologic consult will be requested, and a skin biopsy will be performed to confirm 
the diagnosis. The skin rash will be treated as per standard care and will be followed up 
until resolution regardless of etiology or severity.
3. Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug. Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
4. Pregnancy
5. A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
6. Subjects who develop of any of the following features on MRI should be discussed with 
the medical monitor: 
vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage.  If discontinued from study drug, subjects 
will undergo an ED Visit within 7 days after discontinuation.  They will also undertake 
an Unscheduled (UNS) Visit (with MRI) at approximately 4 weeks after the visit at 
Page 179 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 153 of 164
which such MRI features were first identified.  Additional visits for safety may be 
arranged if clinically indicated in the opinion of the investigator, including after 12 weeks 
after the last dose of study drug.  At any time during the Treatment Period, subjects who 
have asymptomatic, treatment-emergent microhemorrhages as detected by MRI, but none 
of the features which merit discontinuation of treatment (ie, vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic treatment-emergent 
microhemorrhage) may continue with treatment.  These subjects will have safety 
assessments (including MRI) at approximately 4 weeks after the visit at which such MRI 
features were found.  They will also continue with the scheduled MRI scans.  Additional 
unscheduled MRI scans may be arranged on an individual subject basis in discussion 
with the study medical monitor.  
7. Subjects who have postdose ECG with an average QTcF interval >500 msec from 
triplicate ECGs should be discussed with the medical monitor.
Treatments
During the Extension Phase, all subjects will receive open-label elenbecestat 50 mg once 
daily (QD).  Each subject will take 1 tablet orally QD, with or without food. Please refer to
Table 14 for specific information on drug administration on days when PD sampling is to be 
performed. 
EXTENSION PHASE ASSESSMENTS
Safety assessments will continue to be monitored according to the Schedule of Assessments 
and all adverse events (AEs) and serious adverse events (SAEs) recorded.  All safety 
assessments (eg, physical examinations, neurological examinations, vital signs, hematology, 
blood chemistry, serum and urine pregnancy test for females of childbearing potential, safety 
MRI and vMRI) will be performed as described in Table 14.  The number of blood samples 
and the total volume of blood that will be collected throughout Extension Phase are
summarized in Table 13.  
There will be no centralized dermatological assessments in the Extension Phase; however, 
dermatological assessments will be performed by the investigator at every scheduled visit 
and as needed, at a UNS Visit. These assessments will specifically include evaluation of any 
areas of depigmentation or drug-induced vitiligo as well as any evidence of rash. Subjects 
will also be questioned by the investigator at each visit to identify any changes that might 
represent a drug-induced rash/reaction or infection. 
Subjects and their caregivers or 
informants will be instructed to contact the investigator if they see any lesions or other 
symptoms that might be associated with a drug-induced rash/reaction or infection, so that 
such AEs can be reviewed promptly. 
Full neurologic examinations will be performed at the start of the Extension Phase (Visit 20 
or 21), and every 6 months during the first 24 months of the Extension Phase Treatment 
Page 180 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 154 of 164
Period and every 12 months thereafter.  An additional neurologic examination will also be 
performed at the final Follow-up Visit. The neurologic examinations will include muscle 
strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Smell Identification Test, as well as other parts of the central nervous system (CNS).
Complete blood counts and percentages will be measured (by a centralized laboratory) every 
scheduled visit.  Additional blood sample will be collected and stored; these samples may be 
used for exploratory biomarker analyses or be analyzed in the event that the subject develops 
treatment-emergent adverse events (TEAEs) that warrant further investigation.
Peripheral blood mononuclear cells (PBMCs) will be collected at baseline (Visit 21), Month 
6 (Visit 26), Month 12 (Visit 28), and Month 24 (Visit 32) only for exploratory 
immunomodulatory and immune-based analyses.  These blood samples will be collected at 
the specified visits and stored in the event that the subject develops TEAEs that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to 
determine whether the subject already had prior exposure to any suspected infective agents.
Safety brain MRI and vMRI assessments will be performed at Month 24 (Visit 32) and 
Month 48 (Visit 38) of the Extension Phase Treatment Period. Subjects who discontinue 
early from the Extension Phase will have safety brain MRI and vMRI assessments at the ED 
Visit if these assessments have not already been performed during the preceding 90 days.  If 
subjects have non-MRI compatible devices fitted during treatment, then a computed 
tomography scan may be utilized to assess safety, if deemed appropriate by the investigator.  
Additional safety MRI scans are to be performed as clinically necessary.  MRI acquisition 
and interpretation will be organized centrally to ensure reproducibility and consistency 
between units involved.  
Assessment of suicidal ideation and behavior using the C-SSRS will be performed at the start 
of the Extension Phase (Visit 21) and at Month 24 (Visit 32) and Month 48 (Visit 38) of the 
Extension Phase Treatment Period.  Subjects who discontinue early from the Extension 
Phase will have assessments of suicidality using C-SSRS at the ED Visit. 
Clinical 
assessment of suicidality, collected from both the subject and the caregiver/informant, will be 
performed at every scheduled interim safety visit that do not include administration of the 
C-SSRS.  At these visits, a positive suicidality assessment from the subjects or their 
caregiver/informant on the clinical assessment of suicidality (ie, “yes” response on the 
clinical assessment of suicidal thinking and behavior) will trigger the C-SSRS to be 
administered.  
Blood sample for PD analyses will be collected at start of the Extension Phase (Visit 20 or 
21), Month 12(Visit 28), Month 24 (Visit 32), Month 36 (Visit 35), and Month 48 (Visit 38
or ED Visit), and during the Follow-up Period (at 4 and 12 weeks after last dose of study 
drug in the Extension Phase). The plasma sample will be used for Aβ(1-x) analysis and may 
be used for exploratory biomarker analyses.  The blood sample for PD analyses should be 
collected at fasting or at least 2 hours after the most recent meal.
Page 181 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 155 of 164
Clinical assessments (MMSE and FAQ) will be administered every 3 months for the first 
24 months and every 4 months thereafter, as described in Table 14.
The Follow-up Visit will take place at Weeks 4 and 12 after the last dose of study drug as 
described in Table 14.  These assessments will also be performed if a subject prematurely 
discontinues from the Extension Phase.
Table 13
Summary of Blood Sample Volumes for Extension Phase
Assessment
Total number of 
collection time pointsa
Number of time points x 
volume per collection (mL)
Total volume (mL)
Extension Phase Treatment 
and Follow-up Periods
Blood
Clinical Chemistry
21
21 x 2 mL
42 mL
Hematology
21
21 x 5 mL
105 mL
Lymphocyte subset 
analysesb
8
8 x 4 mL
32 mL
PBMC
4
4 x 16 mL
64 mL
PT, PTT for INR
1
1 x 3 mL
3 mL
Serum Pregnancy
Test
1
1 x 2 mL
2 mL
Sample for immune 
statusc
10
10 x 4 mL
40 mL
PD sample
8
8 x 4 mL
32 mL
Total volume whole blood collected
320 mL
PBMC = peripheral blood mononuclear cell, PT = prothrombin time, PTT = partial thromboplastin time, INR = International 
Normalized Ratio, PD = pharmacodynamics.
a:
Total collection time points include a baseline sample at Visit 21 if not done at Visit 20; a baseline sample will be 
collected only if Visit 21 is conducted more than 10 days after Visit 20.
b:
Blood samples for lymphocyte subset analyses will be collected and analyzed at every visit during the first 12 months 
only; reports of the analyses will be sent to the sponsor only.  
c:
Blood samples for immune status will be collected and stored.  These samples may be used for exploratory biomarker 
analyses, or in the event that the subject develops treatment-emergent adverse events that warrant further investigation 
(eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior 
exposure to any suspected infective agents.
STUDY DRUG SUPPLIES 
Elenbecestat (E2609) tablets of 50-mg dose strengths will be supplied.  Each subject will 
take 1 tablet per day.
SCHEDULE OF PROCEDURES/ASSESSMENTS
Table 14 presents the Schedule of Procedures/Assessments for the Extension Phase. 
Page 182 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 156 of 164
Table 14 Schedule of Procedures/Assessments in Study 202:  Extension Phase
Phase
Extension Phase
Period
Treatment
Follow-Upd
UNS 
Visite
Visita
21b
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
EDc
Wk 4
Wk 12
Ext Day 
1
15
29
57
85
183
274
365
456
547
638
729
848
974
1093
1212
1338
1457
1485
1541
Ext Week
1
3
5
9
13
27
40
53
66
79
92
105
122
140
157
174
192
209
213
221
Weeks elapsed 
since 1st Ext dose
0
2
4
8
12
26
39
52
65
78
91
104
121
139
156
173
191
208
212
220
Nominal months 
elapsed since 1st 
Ext dose
0
1
2
3
6
9
12
15
18
21
24
28
32
36
40
44
48
49
51
Procedures/
Assessments
Routine physical 
examination with 
dermatologic 
review
Xf,g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Inclusion and 
Exclusion criteria
X
Vital signs, 
including 
respiratory ratei
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Weight
Xf
X
X
X
X
X
X
Neurological 
examinationk
Xf
X
X
X
X
X
X
X
X
X
Concomitant 
medicationsl
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGn
Xf
X
X
X
X
X
X
X
X
X
Xh
X
Clinical 
biochemistry and 
urinalysis
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood 
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 183 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 157 of 164
Phase
Extension Phase
Period
Treatment
Follow-Upd
UNS 
Visite
Visita
21b
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
EDc
Wk 4
Wk 12
Ext Day 
1
15
29
57
85
183
274
365
456
547
638
729
848
974
1093
1212
1338
1457
1485
1541
Ext Week
1
3
5
9
13
27
40
53
66
79
92
105
122
140
157
174
192
209
213
221
Weeks elapsed 
since 1st Ext dose
0
2
4
8
12
26
39
52
65
78
91
104
121
139
156
173
191
208
212
220
Nominal months 
elapsed since 1st 
Ext dose
0
1
2
3
6
9
12
15
18
21
24
28
32
36
40
44
48
49
51
Procedures/
Assessments
count
Blood sample for 
PT and PTT for 
INR
X
Blood samples for 
lymphocyte subset 
analysiso
Xj
X
X
X
X
X
X
X
Blood samples for 
PD and 
exploratory 
biomarkersp
Xf
X
X
X
X
X
X
X
X
Blood samples 
(isolation of 
PBMCs)
Xf
X
X
X
Urine pregnancy 
test (females of 
CBP only)q
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy 
test (females of 
childbearing 
potential only)
X
X
Blood sample 
(storage for 
Xf
X
X
X
X
X
X
X
X
X
X
Page 184 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 158 of 164
Phase
Extension Phase
Period
Treatment
Follow-Upd
UNS 
Visite
Visita
21b
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
EDc
Wk 4
Wk 12
Ext Day 
1
15
29
57
85
183
274
365
456
547
638
729
848
974
1093
1212
1338
1457
1485
1541
Ext Week
1
3
5
9
13
27
40
53
66
79
92
105
122
140
157
174
192
209
213
221
Weeks elapsed 
since 1st Ext dose
0
2
4
8
12
26
39
52
65
78
91
104
121
139
156
173
191
208
212
220
Nominal months 
elapsed since 1st 
Ext dose
0
1
2
3
6
9
12
15
18
21
24
28
32
36
40
44
48
49
51
Procedures/
Assessments
immune status)r
MMSEs
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FAQs
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
Xf
X
X
X
X
Clinical 
assessment of 
suicidal thinking 
and behaviort
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety MRI and 
vMRIu
Xf
X
X
X
X
Adverse events
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
drug
Xv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Notes for Table 14
C-SSRS = Columbia Suicide Severity Rating Scale, ED = Early Discontinuation, Ext = Extension Phase, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), INR = International Normalized Ratio; MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PBMC = 
peripheral blood mononuclear cell, PD = pharmacodynamics, QTcF = QTc with Fridericia correction; UNS = unscheduled, vMRI = volumetric magnetic resonance imaging, 
Wk = week.
a:
A window of ±3 days will be permitted for Visits 22 and 23.  A window of ±7 days will be permitted for Visits 24 and 25.  A window of ±10 days will be permitted for 
Visit 26 to 38 inclusive.  A window of ±3 days will be permitted for the Follow-up Visits.  If a permitted visit window is used, every effort should be made to bring the 
Page 185 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 159 of 164
subject back in line with the “weeks elapsed since 1st dose in Extension Phase” at subsequent visits.
b:
Visit 21 may occur on the same day or within 4 weeks of Visit 20 date.  The Medical Monitor must be contacted if Visit 21 is to occur more than 4 weeks after Visit 20.  
Informed consent must be obtained before performing Visit 21 assessments.
c:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-up 
Visits will be scheduled 4 and 12 weeks after the last dose of study drug.
d:
All subjects, regardless of whether they complete all 48 months of treatment or discontinue study drug prematurely, will complete the 2 posttreatment Follow-up Visits; 
(ie, 4 and 12 weeks after the last dose of study drug). If clinically indicated, more frequent safety assessments can be made as UNS assessments or visits during the 
posttreatment Follow-up Period.
e:
Unscheduled visits may be conducted at any time that additional assessments, including MRI scans, are clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific 
visit needs.
f:
Result from Visit 20 will also serve as Visit 21 result.  If the specified assessment was not performed at Visit 20, it must be performed at Visit 21.
g:
Dermatologic assessment by the investigator must be performed at Visit 21 in addition to the centralized skin assessment (using standardized photography) performed at 
Visit 20.
h:
Only if clinically significant abnormalities are found at the Follow-up Week 4 Visit and the investigator considers it necessary to repeat at the Follow-up Week 12 Visit.
i:
Measurements of body temperature and sitting blood pressure and sitting heart rate will be obtained.
j:
Result from Visit 20 will also serve as Visit 21 result if Visit 21 occurs within 10 days from Visit 20.  If Visit 21 occurs more than 10 days after Visit 20, the assessment 
must be repeated at Visit 21.
k:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive 
decline in excess of expectations based on the subject’s recent history.  The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and 
serves as part of the neurologic examination.
l:
Please refer to Section 9.4.7, which describes prohibited and permitted medications in the study.
m:
Result from Visit 20 will also serve as Visit 21 result if Visit 21 occurs on the same day as Visit 20.  If Visit 21 occurs more than 1 day after Visit 20, the assessment must 
be repeated at Visit 21.
n:
Single 12-lead standard ECGs will be recorded.  If the QTcF is greater than 450 msec, perform 2 more 12-lead standard ECGs 1 minute apart and take the mean of the 
3 QTcF values. 
o:
Reports of the lymphocyte subset analyses will be sent to the sponsor only.  Lymphocyte subsets will include but are not limited to the following cell surface marker 
assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and absolute lymphocytes.  Regulatory 
T cells will also be measured.  Viability staining may also be employed.
p:
PD blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at the same time of day.  
All PD blood samples should be collected predose.
q:
If dipstick urinalysis performed at site is abnormal,a serum pregnancy test should be performed. 
r:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior 
Page 186 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 160 of 164
exposure to any suspected infective agents.
s:
The subject components of these assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  Ideally, the subject 
component of these assessments should be completed before more invasive assessments or procedures (eg, physical examination, ECG, blood draws).  
t:
The clinical assessment of suicidality will require input from both the subject and the caregiver/informant.  A positive suicidality assessment from the subject or their 
caregiver/informant on the clinical assessment of suicidality (ie, a “yes” response on the clinical assessment of suicidal thinking and behavior) will trigger the C-SSRS to 
be administered.
u:
MRI imaging will be conducted on separate days from the scheduled visits.  Safety MRIs will be acquired using a standardized procedure that will include gradient echo, 
long tau inversion recovery, and diffusion-weighted imaging sequence images in MRI will be read by an approved central reader.  MRI imaging should be conducted 
within 7 days before Visits 21 (where applicable), 32, and 38.  In the event of an UNS Visit, the investigator in consultation with the sponsor will determine whether or not 
a safety MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  
v:
The subject will take the first dose of study drug at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined by 
the investigator or Safety Physician for postdose medical observation.  Subjects with pending INR and serum pregnancy results may begin dosing at Visit 21 if they satisfy 
all other Extension Phase entry criteria.
Page 187 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 161 of 164
EXTENSION PHASE STATISTICAL METHODS
Primary Endpoint

Safety endpoints: AE, vital sign, ECG, physical examination, clinical laboratory test, 
any relevant test of cognitive function to evaluate decline, and MRI parameter 
(microhemorrhage, vasogenic edema, and other clinically significant abnormalities).
Secondary Endpoint
Changes from Core Study and Extension Phase baselines in 

MMSE and FAQ at each visit assessed in the Extension Phase

Plasma amyloid measurements at 12,24, 36, and 48 months of Extension Phase 
treatment

vMRI parameters including, but not limited to, total hippocampal volume, left and 
right hippocampal volume, whole brain volume, and total ventricular volume with up 
to 24 and 48 months of Extension Phase treatment 
EXTENSION PHASE ANALYSIS SETS

The Extension Phase Safety Analysis Set (OLE-SAS) is the group of subjects who 
receive at least 1 dose of study drug during the Extension Phase and who had any on 
therapy safety data during Extension Phase.  

The Extension Phase Full Analysis Set (OLE-FAS) is the group of subjects who 
receive at least 1 dose of study drug during the Extension Phase and have at least 1 
postdose efficacy assessment during the Extension Phase.

The Extension Phase PD Analysis Set is the group of subjects who have at least 1 
posttreatment PD measurement in the Extension Phase.
Safety Analyses
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be 
based on OLE-SAS.  The incidence of AEs (including changes from baseline in physical and 
neurological examinations, and dermatological assessments), out-of-normal-range laboratory 
safety test variables, abnormal ECG findings, out-of-range vital signs, suicidality (C-SSRS
and clinical assessment of suicidality), and changes from baseline in laboratory safety test 
variables, ECGs, safety MRI, vital sign measurements, and cognitive decline assessment 
such as MMSE will be summarized by using descriptive statistics.  
Page 188 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 162 of 164
Efficacy Analyses
The following secondary efficacy endpoints will be summarized by descriptive statistics 
and/or graphs, using OLE-FAS:

Changes from Core Study and Extension Phase baselines in MMSE and FAQ scores

Changes from Core Study and Extension Phase baselines in vMRI parameters 
including, but not limited to, total hippocampal volume, left and right hippocampal
volume, whole brain volume, and total ventricular volume at 24 and 48 months 
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis.
Pharmacodynamic Analyses
The OLE PD Analysis Set will be used for the summaries and analyses of PD biomarkers. 
The percentage change in plasma amyloid measurements from Core Study and Extension 
Phase baselines to 12, 24, 36, and 48 months of Extension Phase treatment will be analyzed 
and presented graphically.
SAMPLE SIZE RATIONALE
Subjects who complete the Core Study will have the option to participate in the Extension 
Phase.  There is no sample size calculation for the Extension Phase.
  
Page 189 of 1658


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 163 of 164
PROTOCOL SIGNATURE PAGE
(revised per Amendment08)
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and
Tolerability of Elenbecestat (E2609) in Subjects With Mild 
Cognitive Impairment due to Alzheimer’s Disease (Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigational Product
Name:
Elenbecestat (E2609)
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neurology Business Group, Eisai Ltd
Date
 Neurology Business Group, Eisai Inc.
Date
 Neurology Business Group, Eisai Inc.
Date
 Neurology Business Group,
Eisai Inc.
Date
Page 190 of 1658
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 08)
E2609-G000-202
Eisai
FINAL (V10.0):  10 Dec 2018
Confidential
Page 164 of 164
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and 
Tolerability of Elenbecestat (E2609) in Subjects With Mild 
Cognitive Impairment due to Alzheimer’s Disease (Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigational Product 
Name:
Elenbecestat (E2609)
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 191 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page i of xxiii
REVISION HISTORY
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
An editorial revision was made 
to add “elenbecestat”, the 
proposed International 
Nonproprietary Name (pINN) 
for “E2609”; grammatical, 
typographical, and formatting 
changes were also made.
The revision was made to provide 
consistency for current and future 
elenbecestat (E2609) clinical 
development documents.
All sections of the 
protocol that previously 
included “E2609” or 
required editorial revision
A Open-label Extension (OLE) 
Phase of up to 24 months was 
added to the protocol specifying 
that eligible subjects who elect 
to continue open-label treatment 
after completing Visit 20 will 
receive elenbecestat (E2609)
50 mg per day. A detailed 
description of the OLE Phase 
was added in Appendix 6.
An editorial revision was made 
referring to the original “study” 
(Prerandomization amd 
Randomization Phases) as the 
“Core Study”.
The OLE was added to assess long-
term safety and tolerability of 
elenbecestat (E2609) 50 mg per day 
in subjects who elect to continue 
open-label treatment after Visit 20.  
The editorial revision was made for 
clarity of presentation where 
description of the OLE procedures 
have been added.
Synopsis 
Study Period and 
Phase of 
Development
Objectives
Study Design
Inclusion Criteria
Exclusion Criteria 
Study Treatment 
Duration of 
Treatment
Concomitant 
Drug/Therapy
Assessments
Endpoints
Analysis Sets
Analyses
Section 7
Section 8
Section 9.1
Section 9.2.4.3
Section 9.2.4.4
Section 9.2.5
Section 9.3
Section 9.3.3
Section 9.4.1
Section 9.4.7
Section 9.5.1.2.1
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.1.4.2
Page 192 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page ii of xxiii
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Section 9.5.1.5
Section 9.5.2
Section 9.5.4.1
Section 9.5.5
Section 9.7.1
Appendix 6
Addition of the OLE Phase to 
evaluate the long-term safety 
and tolerability of elenbecestat
(E2609) and cross reference to 
the detailed OLE Phase protocol 
in Appendix 6.
To add the OLE Phase in the 
context of the elenbecestat (E2609)
clinical development program and 
study design to provide 
investigators with the location of 
the complete detailed OLE Phase 
protocol.
Section 7
Section 9.1
Section 9.1.3
Addition of cross reference to 
objectives for OLE Phase 
protocol in Appendix 6.
To provide investigators with the 
location of the OLE Phase 
objectives.
Section 8
Safety aspects have been built 
into the study design in light of 
the preclinical and clinical 
safety data with elenbecestat 
(E2609) to mitigate clinical risk 
are extended to the OLE Phase 
and 2 off-treatment Follow-Up 
Visits at 4 and 12 weeks after 
the last dose of study drug 
during the OLE Phase are 
added.
To provide instruction to 
investigators for continued 
monitoring procedures for 
mitigation of potential clinical risk
associated with elenbecestat
(E2609).
Section 9.2.5
Section 9.3.3
Section 9.5.1.5.7
Section 9.5.5
Addition of requirement that 
subjects meet all inclusion 
criteria and not meet any of the 
exclusion criteria for the OLE 
Phase, with cross reference to 
the criteria for the OLE Phase in 
Appendix 6.
To provide investigators with the 
requirements for subject elegibility 
and the location of the OLE Phase 
inclusion and exclusion criteria.
Section 9.3
Addition of cross reference to 
criteria for discontinuation of 
study drug during the OLE 
Phase in Appendix 6.
To provide investigators with the 
location of the criteria for 
discontinuation of study drug 
during the OLE Phase.
Section 9.3.3
Prior and concomitant therapy 
restrictions are extended to the 
OLE Phase.
To provide instruction to 
investigators for prior and 
concomitant therapy during the 
OLE Phase.
Section 9.4.7
Page 193 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page iii of xxiii
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Addition of cross reference to 
Table 14.
To direct the investigators to the 
detailed OLE Phase Schedule of 
Procedures/Assessments in 
Study 202:  Open-label Extension 
Phase (Visit 21 through Visit 32).
Section 9.5.1.2.1
Section 9.5.1.3.1
Section 9.5.1.3.2
Section 9.5.1.4.2
Section 9.5.1.5
Section 9.5.1.5.1
Sections 9.5.1.5.3 to 
9.5.1.5.11
Section 9.5.2
Section 9.5.5
Addition of requirement to 
report all adverse events (AEs) 
observed during the OLE Phase; 
clarification that Visit 20 is the 
last visit for subjects who do not 
enter the OLE Phase and that 
Visit 34 is the last study visit 
for subjects who enter the OLE 
Phase.
Added for clarification.
Section 9.5.1.5.1
Removed instructions for SAE 
reporting outside of the 
reporting  period.
To match the standard template for 
SAE reporting.
Section 9.5.1.5.1
Addition of ECG Assessments 
during the OLE Phase.
To specify that a single 12-lead 
ECG will be performed during the 
OLE Phase.
Section 9.5.1.5.6
Addition of Dermatologic 
Assessments during the OLE 
Phase.
To stipulate that evaluation of skin 
assessments will be performed by 
the investigator during the OLE 
Phase.
Section 9.5.1.5.8
Page 194 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page iv of xxiii
Revisions to Version 8.0
New version/date:  Version 9.0/01 Feb 2017 (per Amendment 07)
Change
Rationale
Affected Protocol 
Sections
Addition of requirement to 
report all serious adverse events 
(SAEs) observed during the 
OLE Phase; clarification that 
Visit 20 is the last visit for 
subjects who do not enter the 
OLE Phase and that Visit 34 is 
the last study visit for subjects 
who enter the OLE Phase.
Added for clarification.
Section 9.5.4.1
Addition of cross reference to 
Appendix 6 for discussion of 
OLE Phase statistical analyses.
To provide investigators the 
location of the OLE Phase 
statistical analyses discussion.
Section 9.7.1
The term “total lymphocyte
count” was changed to
“absolute lymphocyte
count”.
To ensure consistency throughout 
the protocol and consistency with 
reports generated by the central 
laboratory.
Synopsis 
Concomitant 
Drug/Therapy
Section 9.2.5
Section 9.4.7
Section 9.5.1.5.3
Table 7
Appendix 2
Page 195 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page v of xxiii
Revisions to Version 7.0
New version/date:  Version 8.0/02 Nov 2016 (per Amendment 06)
Change
Rationale
Affected Protocol 
Sections
Subjects currently receiving 5 
or 15 mg elenbecestat (E2609)
will be re-assigned to 50 mg 
elenbecestat (E2609) for the 
remainder of the double-blind 
treatment period provided they 
will receive at least 12 weeks of 
double-blind treatment after the 
re-assignment, (ie, no dose 
reassignments past Visit 17).
As elenbecestat (E2609) 50 mg has 
been selected as the appropriate 
dose for Phase 3 development, 
subjects should not continue with 
doses that are not being advanced 
clinically. Additionally, the 
re-assignment of subjects in
elenbecestat (E2609) 5 and 15 mg 
to elenbecestat (E2609) 50 mg will 
further the safety and tolerability 
data in subjects exposed to 
elenbecestat (E2609) 50 mg.
Synopsis 
Study Design
Number of Subjects
Sample Size 
Rationale
Section 7.1
Section 9.1
Section 9.1.2.1
Section 9.4.1
Section 9.4.4
Section 9.5.2
Clarified that one of the 
exploratory endpoints will 
analyze  change from baseline 
in CSF amyloid and CSF 
BACE1 measurements from 
4 weeks and up to 18 months of 
treatment  only.  There will no 
analysis for treatment follow-
up.
Correction
Synopsis 
Analysis for 
Exploratory 
Endpoints
Exploratory 
Objective
Section 8.3
Section 9.7.1.1.3
Section 9.7.1.6.3
The frequency of DSMB safety 
reviews after the 12 week 
interim safety analysis will be 
reassessed and details will 
provided in the DSMB charter.
The DSMB charter will provide full 
details of interim safety reviews.
Synopsis 

Study Design
Section 9.1
Removed the statement that 
subjects must be stable on 
acetylcholinesterase inhibitor
(AChEI) or mementine to be 
included in the primary 
analyses.
This statement is no longer relevant 
as of Amendment 05.
Synopsis 
Concomitant 
Drug/Therapy
Section 9.4.7
Added a statement to specify 
that additional analyses will be 
performed for subjects with
dose re-assignment and details 
of these analyses and treatment 
group definitions will be 
provided in the statistical 
analysis plan (SAP); clarified 
that the  SAP will be finalized 
before database lock.
To clarify that the SAP will be 
finalized prior to database lock and 
it will provide full details of the 
analyses to be performed for this 
study. 
Section 9.7.1
Page 196 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page vi of xxiii
Revisions to Version 6.0
New version/date:  Version 7.0/26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Removed Stage B from protocol. In 
line with this decision, the study 
objectives and endpoints have been 
modified and subjects who 
discontinue study drug early for any 
reason will no longer be required to 
complete efficacy visits after last 
dose of study drug.
This study will no longer 
be a Proof-of-Concept 
study.  
Synopsis 
Study Protocol Title
Investigators
Sites
Study Period and Phase 
of Development
Objectives
Study Design
Early Discontinuation
Number of Subjects
Study Treatments
Efficacy Assessments
Safety Assessments
Statistical Methods
Study Endpoints
Analysis Sets
Efficacy and Biomarker 
Analyses
Analysis for the 
Primary/Secondary/Explo
ratory Endpoints
Pharmacokinetic 
Analyses
Pharmacokinetic 
/Pharmacodynamic 
Analyses
Interim Analyses
Sample Size Rationale
Section 6
Section 7
Section 8
Section 8.3
Section 9.1
Section 9.2.1
Section 9.2.3
Section 9.2.4.4
Section 9.2.5
Section 9.3
Page 197 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page vii of xxiii
Revisions to Version 6.0
New version/date:  Version 7.0/26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Section 9.4.3
Section 9.4.4
Section 9.4.7
Section 9.2.5
Section 9.5.1.3.1
Section 9.5.1.4.2
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.4.1
Section 9.5.5
Section 9.7
Section 10
Updated Eisai contact information 
Change in personnel and 
move to Building 100
Title Page
Protocol Signature Page
Page 198 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page viii of xxiii
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of investigational 
sites (from 40 to 35)
Feasibility

Synopsis -
o Study Design
o Sites
Section 6
Section 9.1
Section 9.3
Removed Exclusion Criterion No. 
44 for male subjects regarding 
restrictions on child bearing  
No longer a safety concern;
E2609 has not shown a 
deleterious effect on sperm in 
preclinical reproductive toxicity 
studies.

Synopsis:
o Exclusion Criteria
Section 9.3.2
Added option for subjects who 
provided a CSF sample prior to 
randomization but who declined the 
CSF sample collection after 4 weeks 
of dosing to provide a postdose CSF 
sample at any point in the study (ie, 
even after 4 weeks of dosing).
Reflects the added value of CSF 
data for the PK/PD secondary 
objective of this study.  In 
addition, given that PK steady 
state is achieved within the 1st 
2 weeks of initiation of dosing, 
data collected post Week 4 visit 
is still considered to be 
applicable in assessment of the 
steady state effect.

Synopsis -
o Pharmacodynamic
Assessments
Section 5.3
Section 9.1
Section 9.1.1.2
Section 9.5.1.3.3
Section 9.5.1.4
Table 6
Table 7
Table 8
Revised details of restrictions to 
anticoagulant therapy and short-
term steroid use revised/moved 
details regarding antiplatelet drugs 
to the main body of the protocol
To assist in subject recruitment 
and retention and considering 
that the strict restrictions were 
not necessary for subject safety

Synopsis -
o Concomitant 
Drug/Therapy
Section 9.4.7
Appendix 2
Removed the 33% decrease from 
baseline for CD4, CD8, and CD19 
as a trigger for more frequent 
testing of flow cytometry and 
CBCs. Additional safety 
monitoring for CD4, CD8, CD19, 
and CBCs will only be based on the 
population adjusted LLNs for 
clinically asymptomatic subjects. 
Experience to date has indicated 
significant variability within the 
normal range, both for increases 
and decreases. Absolute counts 
of lymphocyte subsets are more 
meaningful than percentage 
decreases for triggering more 
frequent monitoring.
Section 9.3.3
Table 1
Table 2
Page 199 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page ix of xxiii
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Added option to temporarily 
suspend study drug for subjects who 
are clinically asymptomatic but who 
meet CD4, CD8, or CD19 
discontinuation thresholds on 
2 consecutive tests.  Introduce rules
for ability to re-start study drug (ie, 
rechallenge) in these subjects.   
Only 1 cycle of temporary 
suspension and rechallenge with 
study drug permitted for any 
individual subject.  
To assist in subject retention and 
to gain knowledge on the 
behavior of lymphocyte subsets 
on rechallenge.
Section 9.3.3
Table 1
Table 2
Added extra blood draw times with 
focus on lymphocyte subsets, 
CBCs, and immunoglobulins during 
the 12-week safety follow-up for all 
subjects.
To increase frequency of key 
safety monitoring parameters in 
post-treatment follow-up period 
so as to assess immunological 
changes after completion of 
study drug

Synopsis
o Study Design
o Safety Assessments
Section 9.1.2.2
Section 9.1.2.3
Section 9.2.5
Section 9.3.3
Table 7
Table 8
Section 9.5.1.5.7
Section 9.5.5
Clarified that the Functional 
Assessment Questionnaire is to be 
administered to the 
informant/caregiver, and not the 
subject.
Clarification

Synopsis
o Efficacy 
Assessments
Section 9.5.1.3.1
Added clarification that the Brief 
Smell Identification Test will be 
administered as part of the 
neurological examination
Clarification

Synopsis
o Safety Assessments
o Interim Analyses
Section 9.1.1.2
Section 9.5.1.2.1
Section 9.5.1.5.9
Table 6
Table 7
Page 200 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page x of xxiii
Revisions to Version 5.0
New version/date:  Version 6.0/29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of randomized 
subjects in Stage A to n=60±20%
To allow for additional 
randomization based upon 
current number of subjects in 
screening at the time of 
amendment implementation

Synopsis
o Study Design
o No. of Subjects
Section 7
Section 9.1
Section 9.2.1
Section 9.2.5
Section 9.3
Section 9.7.3
Grammatical, typographical, and 
formatting corrections
Consistency
various
Page 201 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xi of xxiii
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder of 
the study and the full 
elenbecestat (E2609)
clinical development 
program

Synopsis –
o Exploratory Endpoint 
Analysis
o Interim Analysis
Section 9.1
Section 9.1.1.2
Section 9.4.6
Section 9.7.1.7.1
Page 202 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xii of xxiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.5
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Appendix 2, Listing 2
Page 203 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xiii of xxiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
o
Inclusion/Exclusion
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.4.3

Section 9.3.1

Section 9.5.2

Table 6

Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/Exclusion

Section 9.3.2

Section 9.5.2

Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
Added to provide clarity 

Synopsis –
Page 204 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xiv of xxiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
for the sites.
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1

Figure 2

Section 9.5.1.3.1

Section 9.5.2

Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3

Table 1

Section 9.5.2

Table 6

Table 7
Page 205 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xv of xxiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1

Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2

Table 6
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2

Table 6

Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3

Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2

Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2

Table 6

Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 206 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xvi of xxiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1

Section 9.1.1

Figure 1

Section 9.2.1

Section 9.2.2

Section 9.2.3

Section 9.2.4.3

Section 9.2.4.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.4.3

Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2

Section 9.7.1.1.3

Section 9.7.1.4

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.3

Section 9.7.4
Page 207 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xvii of xxiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 

Section 5.3
Page 208 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xviii of xxiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
capacity to consent themselves.
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis –
o
Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 209 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xix of xxiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis –
o
Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis –
o
Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis –
o
Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
o
Inclusion/Exclusion  
Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and  
International Normalized Ratio 
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
o
Inclusion/Exclusion 
Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –
o
Study Design  

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1
Page 210 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xx of xxiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
of efficacy assessments.

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol.  The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20 
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis –
o
Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis –
o
Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis –
o
Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline, 
during treatment, and post-
treatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF 
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis –
o
Assessments

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis –
o
Concomitant 
Drug/Therapy

Section 7.1
Page 211 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xxi of xxiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors

Section 9.4.7

Appendix 2, Listing 6
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis –
o
Analysis of Primary 
Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis –
o
Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 
abuse potential.  No longer use the 

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5.1
Page 212 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xxii of xxiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis –
o
Study Endpoints

Section 9.7.1.2
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.5

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Page 213 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page xxiii of xxiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 214 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 1 of 164
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-
Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects 
With Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
Elenbecestat * (E2609)
* the proposed International Nonproprietary Name (pINN) (revised per 
Amendment 07)
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
V6.0
29 Jun 2016 (Amendment 04)
V7.0
26 Sep 2016 (Amendment 05)
V8.0
02 Nov 2016 (Amendment 06)
V9.0
01 Feb 2017 (Amendment 07)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Page 215 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 2 of 164
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.
Page 216 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 3 of 164
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-Finding Study To Evaluate 
the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01and 05)
Investigators
Investigators in the United States only (revised per Amendment 05)
Sites
Approximately 35 sites, United States only (revised per Amendments 01, 02, 04, and 05)
Study Period and Phase of Development (revised per Amendment 07)
This Phase 2 study will include the following:
Core Study: approximately 32 months including the Prerandomization and Randomization 
Phases (revised per Amendments 05 and 07)
Open-label Extension (OLE) Phase: approximately 27 months including 24 months of 
treatment period and 3 months of off-treatment follow-up period (revised per Amendment 
07)
Objectives
Core Study (revised per Amendment 07)
Primary Objective (revised per Amendment 05)
To assess the safety (including immunological and hematological parameters) and tolerability of daily 
dosing with elenbecestat (E2609) in Mild Cognitive Impairment (MCI)/Prodromal subjects and in
subjects with Mild to Moderate Dementia due to Alzheimer's Disease (referred to as mild to moderate 
AD throughout the protocol) (revised per Amendments 01 and 07)
Secondary Objectives (revised per Amendments 02 and 05)

To characterize the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of 
elenbecestat (E2609)
To assess the effects of elenbecestat (E2609) on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and up 
to 18 months of treatment 
Exploratory Objectives
(revised per Amendments 01, 02, 04, and 05)

To explore the effects of elenbecestat (E2609) on CSF Aβ(1-40) and beta (β)-amyloid 
converting enzyme 1 (BACE1) measurements from 4 weeks and up to 18 months of 
Page 217 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 4 of 164
treatment

To explore the effects of elenbecestat (E2609) compared with placebo on various biomarkers.  
Biomarkers to be explored may include but are not limited to:
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of elenbecestat (E2609) compared with placebo on clinical status at 
various time points during 18 months of treatment, and during posttreatment follow-up, by 
assessment of: 
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of elenbecestat (E2609) on 
measured clinical efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF 
amyloid isoforms, brain amyloid, and vMRI 

To explore relationships between both elenbecestat (E2609) dose and exposure, with 
pharmacodynamic (PD) and safety endpoints 
Open-Label Extension Phase (revised per Amendment 07)
Primary Objective:

To assess the long-term safety and tolerability of daily dosing with elenbecestat (E2609)
50 mg in MCI/Prodromal subjects and in subjects with Mild to Moderate Dementia due to 
AD
Secondary Objectives

To explore the long-term effects of elenbecestat (E2609) on clinical status by assessment of: 
a.
The MMSE
b.
The FAQ 

To explore the long-term effects of elenbecestat (E2609) on:
a.
vMRI including total hippocampal volume, left and right hippocampal volume, 
whole brain volume, and total ventricular volume with up to 24 months of treatment 
in the OLE Phase.
Page 218 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 5 of 164
b.
Plasma amyloid at 12 and 24 months of treatment in the OLE Phase.
Study Design
This will be a multicenter, placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study with an OLE Phase of up to 27 months in subjects with MCI/Prodromal AD or mild to 
moderate AD.  (revised per Amendment 07)  A common set of inclusion criteria, consistent with the 
National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical research criteria for MCI 
due to Alzheimer’s Disease (AD) or mild to moderate AD, will be required for all subjects.  In 
addition, the MCI due to AD population will also be consistent with the research criterion for 
“Prodromal AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with the criteria for both MCI due to AD and Prodromal 
AD they will be identified as MCI/Prodromal subjects in this protocol.  The diagnosis of 
MCI/Prodromal AD or mild to moderate AD will be based on both clinical and biological (ie, 
confirmation of amyloid load in the brain) criteria.  (revised per Amendment 01)
The study consists of 3 phases:  Prerandomization, Randomization, and OLE.  The Prerandomization 
and Randomization Phases are referred to as the Core Study throughout the protocol. (revised per 
Amendment 07)
Core Study 
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if required 
[revised per Amendment 02]) includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All 
screening assessments (within 4 distinct tiers) must be completed, and eligibility to continue in the 
study confirmed, before any baseline assessments commence.  Following successful completion of 
the Prerandomization Phase, eligible subjects will be randomized and will enter the Randomization 
Phase, which will consist of 2 periods:  Treatment (78 weeks) and Follow-Up (post last dose; 
12 weeks).
The study will be limited to approximately 35 sites in the United States.  (revised per Amendments 
01, 02, and 04)  Subjects will initially be randomized 1:1:1:1 to 4 treatment groups (5, 15, or 50 mg 
elenbecestat [E2609] or placebo) within each of the 2 clinical populations.  (revised per Amendments
01, 04, 05, and 06) In addition to the placebo group, 3 elenbecestat (E2609) doses will be used to 
reduce CSF amyloid β levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from 
baseline, respectively, at steady state. PK/pharmacodynamic (PD) modeling has shown that these 
doses should achieve these targets when administered once daily (QD) with food, and these doses 
will be evaluated based on the 4-week (or later) assessment of CSF Aβ(1-x) from subjects who 
provide voluntary consent for CSF measurement.  (revised per Amendment 02)  Upon 
implementation of Amendment 06, at the next regularly scheduled visit, subjects receiving 
elenbecestat (E2609) 5 or 15 mg who have not yet completed Visit 17 (Week 66), will be re-assigned 
in a blinded manner to elenbecestat (E2609) 50 mg for the remainder of the double-blind treatment 
period. In order to maintain the blind, all subjects who have not yet had Visit 17 will go through the 
same procedures with the placebo-randomized subjects continuing to receive placebo and those 
randomized to elenbecestat (E2609) 50 mg continuing to receive 50 mg. (revised per Amendment 06)
Safety data will be monitored in a blinded fashion on a regular basis.  In addition, approximately 
every 3 months from the time the 1st subject is randomized into the study through the time the last 
subject is randomized, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  (revised per Amendment 06) 
The DSMB will make recommendations to Eisai after each review as to whether any change(s) to the 
study are necessary.  (revised per Amendments 01, 04, and 05)
Interim analyses of the elenbecestat (E2609) plasma PK for all subjects and the elenbecestat (E2609)
Page 219 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 6 of 164
CSF PK and PD profiles will be performed on baseline data and samples collected after at least 
4 weeks of treatment.  (revised per Amendment 05)  These interim analyses, as well as analyses of 
safety data, will be performed on an ongoing basis throughout the study.  Refer to the Interim 
Analysis section for more detail.
These data will be used to evaluate the CSF PD effects of 
elenbecestat (E2609) doses, where PD is measured as reductions from baseline in CSF Aβ(1-x) 
levels.  (revised per Amendments 01 and 02)  The median and mean percentage change from baseline 
in CSF Aβ(1-x) measured after 4 weeks or more of treatment for each dose of elenbecestat (E2609)
and the 90% confidence interval (CI) for the median will be derived. In addition, exploratory PK/PD 
modeling will be conducted.  This PK/PD modeling will use the observed PK and PD data and will 
relate the average steady state plasma concentration of elenbecestat (E2609) to CSF Aβ(1-x) 
percentage reduction from baseline determined after at least 4 weeks of dosing. (revised per 
Amendments 01, 02, 03, 04, and 05)  
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug early) an 
interim safety analysis will be conducted by Eisai and the DSMB. At the completion of this interim 
safety review, the frequency of subsequent unblinded safety reviews will be re-evaluated by the 
DSMB and the Sponsor and this information will be provided in the DSMB charter. (revised per 
Amendment 06) Subjects will continue study drug while the DSMB reviews all the available safety 
data. (revised per Amendments 01, 04, 05, and 6).
Open-Label Extension Phase (revised per Amendment 07)
The OLE Phase allows eligible subjects to receive elenbecestat (E2609) 50 mg daily for up to 24
months (2 years).
All subjects who complete 18 months of treatment and 12 weeks of follow-up in the Core Study and 
who satisfy the entry criteria for the OLE Phase are eligible to enter the OLE Phase. After 
completing all Visit 20 procedures in the Core Study Follow-up Period, eligible subjects will have the 
option to participate in the OLE Phase within 4 weeks of Visit 20 of the Core Study.  These subjects 
may transition to the OLE Phase immediately following Visit 20 (on the same day) if the decision to 
proceed with the OLE Phase has been made at that time.  The Medical Monitor must be contacted if 
Visit 21 is to occur more than 4 weeks after Visit 20.
For all subjects, assessments performed at Visit 20 may serve as Visit 21 (start of the OLE Phase) 
results with the following exceptions: laboratory assessments and vital signs must be repeated if 
Visit 21 occurs more than 10 days from Visit 20.
Subjects who are eligible and who consent to participate in the OLE Phase will be administered 
elenbecestat (E2609) 50 mg daily at Visit 21.  Subjects with pending INR and serum pregnancy test 
results (females subjects of child bearing potential only) but who are otherwise eligible may begin 
OLE dosing at Visit 21; however, these subjects must discontinue study drug treatment immediately 
if either test result meet the exclusion criteria.
During the OLE Phase, safety assessments will continue to be monitored and all AEs and SAEs will 
be recorded.  Vital signs, hematology, blood chemistry, and urine values will be monitored at every 
scheduled visit.  Clinical assessments (MMSE and FAQ) will be administered every 3 months.  Blood 
for PD analyses will be collected every 12 months. All subjects will be assessed using safety MRIs 
and vMRI measurements at the end of the OLE Phase.  
Early Discontinuation (Core Study)
Subjects who prematurely discontinue taking study drug prematurely for any reason during the Core 
Page 220 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 7 of 164
Study will undergo an Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  
Follow-Up Visits will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug.
(revised per Amendments 04 and 05)  
Follow-Up (Core Study)
All subjects, regardless of whether they complete all 18 months of treatment or prematurely
discontinue study drug, will complete 4 post-treatment Follow-Up Visits: 2, 4, 8, and 12 weeks after 
the last dose of study drug.  If clinically indicated, more frequent safety assessments can be 
conducted as part of unscheduled visits during the post-treatment Follow-up Period. (revised per 
Amendment 04)
Early Discontinuation (Open-Label Extension Phase) (revised per Amendment 07)
Subjects who prematurely discontinue study drug for any reason during the OLE Phase will undergo 
an ED Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also be scheduled 
4 and 12 weeks after the last dose of study drug.  
Follow-Up (Open-Label Extension Phase) (revised per Amendment 07)
All subjects, regardless of whether they complete all 24 months of treatment in the OLE Phase or 
prematurely discontinue study drug, will complete 2 posttreatment Follow-Up Visits at 4 and 
12 weeks after the last dose of study drug. (revised per Amendment 07)  If clinically indicated, more 
frequent safety assessments can be conducted as part of Unscheduled Visits during the OLE 
Follow-up Period.  
Number of Subjects
Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be screened to provide 
approximately 60 (±20%) randomized subjects (with a target of approximately 15 subjects per 
treatment arm).  There will be no limit to the number of subjects randomized from either clinical 
cohort. (revised per Amendments 01, 02, 04, and 05)
Inclusion Criteria
Core Study
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01) 
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 standard deviation (SD) from age adjusted norms in 
delayed recall on the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from 
age-adjusted norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT 
immediate recall, or 1 of the learning and memory components of the CBB). (revised per 
Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
Page 221 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 8 of 164
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Open-Label Extension Phase  (revised per Amendment 07)
1.
Subjects who complete the 18-month treatment and the 12-week follow-up period (Visit 20) in 
the Core Study and whose Visit 20 falls within a 4-week window from the start of the OLE Phase 
(Visit 21).  Permission must be obtained from the Medical Monitor if Visit 21 is to occur more 
than 4 weeks from Visit 20.
2.
Subjects must continue to have an identified caregiver or informant who is willing and able to 
provide follow-up information on the subject throughout the course of the OLE Phase.  
Exclusion Criteria (revised per Amendment 04)
Core Study
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
Page 222 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 9 of 164
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and <1 cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures (revised per Amendments 01 
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (< lower limit of normal [LLN]) levels for the testing 
laboratory (if subject is taking vitamin B12 injections, level should be at or above the lower limit 
of normal (LLN) for the testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal malformation 
on physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
Page 223 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 10 of 164
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with: 
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled 
steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL 
respectively.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings.  (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
Page 224 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 11 of 164
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.  Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the 1st dose of study drug.
43. Females of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period and for 
Page 225 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 12 of 164
28 days after study drug discontinuation.
b.
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 days 
after study drug discontinuation.
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the 
same contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Open-Label Extension Phase (revised per Amendment 07)
1.
Subjects who discontinue study drug prematurely during the Core Study are not eligible to 
participate in the OLE Phase.
2.
Subjects with any active infection within 4 weeks of Visit 21. 
3.
Subjects with absolute lymphocyte count below the LLN within 10 days of Visit 21.
4.
Subjects who develop the following conditions from the time of screening for the Core Study to
the start of the OLE Phase: 
a.
Hepatic impairment, with total bilirubin greater than 1.5 × ULN or INR greater than 1.7.  
Subjects with Gilbert’s syndrome need not be excluded on the basis of an elevated 
bilirubin, provided that they have no other signs or symptoms suggestive of hepatic 
impairment
b.
Any contraindications to MRI scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as 
safe for use in MRI scanners)
c.
Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
d.
Immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
e.
Chronic viral hepatitis
f.
TB
g.
Ophthalmic shingles
h.
Ocular HSV infection
i.
Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  

Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled 
by inhaled steroids need not be excluded

Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and 
not on systemic immunosuppressive therapy need not be excluded

Cutaneous manifestations of immunological disease that do not require systemic 
Page 226 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 13 of 164
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted)
j.
Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the skin, or 
localized prostate cancer that did not require systemic therapy; these do not exclude the 
subject from OLE).
5.
Subjects with prolonged QTcF interval at Visit 20 or Visit 21. Subjects with a single 12-lead 
ECG QTcF >450 msec should have 2 additional ECGs performed at least 1 min apart and the 
mean QTcF from the triplicate ECGs should be calculated. Subjects with a mean QTcF value 
>450 msec are not eligible to enter the OLE Phase.
6.
Subjects with significant pathological findings on brain MRI including but not limited to: an area 
of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, 
encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple 
lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white 
matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as 
meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be 
exclusionary).
7.
Subjects who have a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5 at Visit 20 or 
Visit 21 or any suicidal behavior during the study prior to the start of the OLE Phase.
8.
Female subjects of child bearing potential who meet any of the follow criteria:
a.
Do not agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period and for 
28 days after study drug discontinuation
b.
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 days 
after study drug discontinuation
c.
Who do not agree to use the same contraceptive during the study treatment period or for 
28 days after study drug discontinuation.
9.
Females who are lactating or pregnant (as documented by a positive β-hCG or hCG test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Visit 20 or Visit 21.  
10. Subjects with medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are 
not stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments.
11. Any other clinically significant abnormal findings in vital signs, ECGs and laboratory tests that 
would, in the investigator’s opinion, would affect the subject’s safety or interfere with study 
assessments during the OLE Phase.
Study Treatments (Core Study)
Elenbecestat (E2609) tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets to 
match elenbecestat (E2609) will be of identical appearance. Each subject will receive 2 tablets, 
which when combined will make up the required doses of elenbecestat (E2609) or placebo, to be 
administered orally QD with food. (revised per Amendment 05)
Study Treatments (OLE Phase) (revised per Amendment 07)
Elenbecestat (E2609) tablets of 50-mg dose strengths will be supplied during the OLE. Each subject 
Page 227 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 14 of 164
will take 1 tablet orally QD, with food.
Duration of Treatment
Core Study
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising the following: 

Screening and Baseline Periods (Prerandomization Phase): up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, the 
duration of the pre-randomization phase can be extended by up to 4 weeks to allow additional 
time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-up Period (Randomization Phase): 12 weeks (post last dose)
Open-Label Extension Phase (revised per Amendment 07)
The duration of the OLE Phase will be approximately 116 weeks, comprising the following:

Treatment Period:  up to 104 weeks (24 months)

Follow-up Period:  12 weeks (after the last dose)
Concomitant Drug/Therapy (Core Study and Open-label Extension Phase)  (revised per 
Amendments 04 and 07)
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit in the Core Study (for subjects 
participating in the Core Study only) or the last treatment visit in the OLE Phase (for subjects 
participating in the OLE Phase)  (see Appendix 2 for a detailed listing of these agents) (revised per 
Amendment 07):
Drugs that may cause QTc prolongation are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 
Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days (whichever is 
longer) before randomization 
Live vaccines are not permitted within 3 months before randomization.  This does not apply to 
non-live/inactivated vaccines
Ig therapy and biologic drugs are not permitted within 6 months before randomization
Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization.  However, during 
the treatment period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started.  Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly.  Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) absolute lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold (for Core Study only); (4) the investigator considers that the medical 
condition which required treatment with steroids has improved or resolved.  Weekly testing of 
lymphocyte subset counts (for Core Study only) and CBC with differentials (for Core Study and 
Page 228 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 15 of 164
OLE) is required for 4 weeks following resumption of study drug administration.  (revised per 
Amendment 04)
(revised per Amendment 06)
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for any efficacy analyses.  
(revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  
Must be on stable dose for at least 4 weeks before randomization, except for medications that are 
administered as short courses of treatment or which are to be used intermittently as needed.  
Subjects who are on anticoagulants may have a variable dose but should have stable 
anticoagulation control for at least 4 weeks before randomization.  They may be required to stop 
their anticoagulant medication prior to CSF collection and then restart this medication after the 
LP procedure, as per local guidelines.  (revised per Amendment 04)
Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a period 
of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator, 
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks
Antiplatelet therapy: (revised per Amendment 04)
For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any other 
antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and clopidogrel (or 
any other antiplatelet drug which is not aspirin) in combination are also permitted but subjects 
who are on such a combination of antiplatelet drugs may be required to stop 1 or more of these 
antiplatelet drugs before the LP procedure and restart after the LP as per local guidelines.
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, individually 
or in combination, are permitted. 
Assessments
Efficacy Assessments (Core Study)
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.
Mini-Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing. 
International Shopping List Task:  The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
Page 229 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 16 of 164
CogState Brief Battery:  A computer-based battery comprising 4 cognitive tests: 

Detection – a simple reaction time test.  Speed of response is the measure.

Identification – a simple choice reaction time test.  Speed of response is the measure.

One Card Back – a simple working memory test.  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
Functional Assessment Questionnaire:  The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.   The caregiver or informant provides performance ratings on 
10 complex activities of daily living performed within the preceding 4 weeks.  (revised per 
Amendment 04)  
Volumetric Magnetic Resonance Imaging:  vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments (Core Study)
Blood samples will be collected for the determination of the concentrations of elenbecestat (E2609).
For subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of elenbecestat (E2609) concentrations.  (revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed depending on emerging data from other studies with 
elenbecestat (E2609).
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments (Core Study)
Brain atrophy will be measured by vMRI:  see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), (Aβ(1-40), total tau (t-tau), and p-tau will be measured in 
subjects who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and 
activity in CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) may also be 
evaluated in plasma or CSF. (revised per Amendment 04)  Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will 
be approached to consider reconsenting to postrandomization CSF sample collection even if they are 
beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
(revised per Amendment 04)
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group.  (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses. (revised per Amendments 02 and 05)
Apolipoprotein E (ApoE) and N-acetyltransferase 2 (NAT2) genotyping/phenotyping will be 
conducted.  ApoE4 homozygous or heterozygous status versus non-carriers and NAT2 status will be 
used in the statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA sequence 
variability on the absorption, distribution, metabolism, and elimination of elenbecestat (E2609), 
development of adverse events (AEs), as well as the underlying AD. Variations in elenbecestat
(E2609) exposure or the occurrence of AEs observed in the study population may be evaluated by 
Page 230 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 17 of 164
correlation of single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments (Core Study)
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and serious adverse events (SAEs), monitoring of hematology, blood chemistry, 
and urinalysis, measurement of vital signs, regular ECGs, physical and neurological examinations, 
and centralized dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a more detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the 
frequency and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the 1st month, every 2 weeks for the next 2 months 
(Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be 
monitored every 3 months until the end of the Treatment Period and at all 4 Follow-Up Visits at 2, 4, 
8, and 12 weeks after the last dose of study drug.  Serum IgG, IgA, and IgM will be monitored 
monthly for the 1st 3 months, at 6, 12, and 18 months, and at the Follow-Up Visits that occur 4, 8, 
and 12 weeks after the last dose of study drug. (revised per Amendment 04)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments 
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects from whom CSF samples were collected (revised per 
Amendments 02 and 04).  These samples may be tested for exploratory biomarkers associated with 
study drug or disease, or in the event that a subject develops AEs that warrant further investigation 
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected infective 
agents before treatment with study drug).
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurologic examinations will be performed at Baseline, at 6, 12, and 18 months, and at the 4- and 
12-week Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  The neurologic examinations will include 
muscle strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Smell Identification Test, as well as other parts of the CNS. (revised per Amendment 04)
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
Page 231 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 18 of 164
regular intervals throughout the Treatment and Follow-up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Efficacy Assessments (Open-Label Extension Phase) (revised per Amendment 07)
MMSE: A 30-point scale that measures orientation to time and place, registration, immediate and 
delayed recall, attention, language, and drawing.
FAQ:  The FAQ has 10 items concerned with performing daily tasks necessary for independent 
living.  The caregiver or informant provides performance ratings on 10 complex activities of daily 
living performed within the preceding 4 weeks.  
vMRI: vMRI will be used to evaluate disease modification, including the changes from the Core 
Study Baseline and the OLE Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacodynamic and Other Biomarker Assessments (Open-Label Extension Phase) (revised 
per Amendment 07)
Exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) will be evaluated in plasma.
Safety Assessments (Open-Label Extension Phase) (revised per Amendment 07)
All subjects will be assessed for their eligibility to for OLE Phase at Visit 21. Where applicable, 
results of the safety assessments (including laboratory assessment, physical examination, and 
neurologic examination) conducted during Visit 20 will serve as Visit 21 values for the OLE Phase 
with the following exceptions: if Visit 21 occurs more than 10 days after Visit 20, all laboratory 
safety assessments and vital signs must be repeated.
Routine safety assessments will include the monitoring and recording all AEs and SAEs, monitoring 
of hematology, blood chemistry, and urinalysis, measurement of vital signs, regular ECGs, and 
physical, dermatologic and neurologic examinations at regular intervals.  
There will be no centralized dermatological assessments in the OLE Phase. Dermatologic review will 
be conducted as part of the physical examination. These assessments will specifically include 
evaluation of any areas of depigmentation or drug-induced vitiligo as well as any evidence of rash. 
Subjects will also be questioned by the investigator at each visit to identify any changes that might 
represent a drug-induced rash/reaction or infection. Subjects and their study partners will be 
instructed to contact the investigator if they see any lesions or other symptoms that might be 
associated with a drug-induced rash/reaction or infection, so that such AEs can be reviewed promptly.
Full neurologic examinations will be performed at the start of the OLE Phase (Visit 20 or 21) and at 
every 6 months during the OLE treatment period.  An additional neurologic examination will also be 
performed at the final Follow-Up Visit. The neurologic examinations will include muscle strength 
testing and assessment of cranial nerves including olfaction, with the use of the Brief Smell 
Identification Test, as well as other parts of the CNS.  
Complete blood counts and percentages will be measured (by a centralized laboratory) every 
scheduled visit. Lymphocyte subset absolute counts and percentages will also be measured (by a 
central laboratory) and the results will be reviewed by the Sponsor and the members of the DSMB
only.
PBMCs will be collected every scheduled visit and posttreatment for exploratory immunomodulatory 
Page 232 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 19 of 164
and immune-based analyses.  Additional blood samples will be collected and stored; these samples 
may be used for further exploratory biomarker analyses, and/or, in the event that the subject develops 
treatment-emergent adverse events that warrant further investigation (eg, treatment-emergent 
infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
Safety brain MRI and vMRI assessments will be performed at the end of the OLE treatment period 
(Visit 32 or ED Visit). Additional safety MRI scans are to be performed as clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.  
Assessment of suicidality using the C-SSRS at the start of the OLE Phase (Visit 21), at the end of 
OLE treatment (Visit 32 or ED Visit), and at the end of the OLE Phase (Visit 34).  Clinical 
assessment of suicidality will be performed at every visit scheduled interim safety visit during the 
OLE Phase.
Bioanalytical Methods
Plasma and CSF elenbecestat (E2609) concentrations  will be measured by a validated liquid 
chromatography method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and postscreening analysis of CSF Aβ(1-42), Aβ(1-40), 
t-tau, and p-tau will be performed using commercially available ELISAs.  (revised per 
Amendment 04)
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
Study Endpoints (Core Study)
Primary Endpoint

Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) 
and SAEs, laboratory parameters, vital signs, and ECG parameters (revised per Amendment 05) 
Secondary Endpoints 
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after at least 4 weeks and 
18 months of treatment

The population PK parameters of elenbecestat (E2609) in CSF and plasma, including the effect of 
intrinsic and extrinsic factors (including NAT2 phenotype) 
Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
Change from baseline in:

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
Page 233 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 20 of 164
18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment 

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and during 
posttreatment follow-up

CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 18 months of treatment 
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and 18 months as 
measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain amyloid 
levels

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months:  
ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ 
Study Endpoints (Open-label Extension Phase) (revised per Amendment 07)
Primary Endpoint

Safety endpoints: AE, vital sign, ECG, physical examination, clinical laboratory test, any relevant 
test of cognitive function to evaluate decline, and MRI parameters (microhemorrhage, vasogenic 
edema, and other clinically significant abnormalities).
Secondary Endpoints 
Changes from Core Study and OLE baselines in:

MMSE and FAQ at each visit assessed in the OLE Phase

Plasma amyloid measurements at 12 and 24 months of OLE treatment

Total hippocampal volume, left and right hippocampal volume, whole brain volume, and total 
ventricular volume with up to 24 months of OLE treatment as measured by vMRI
Analysis Sets (Core Study)

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postdose exploratory efficacy measurement.  (revised 
per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable elenbecestat (E2609)
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at least 
1 posttreatment PD measurement.
Analysis Sets (Open-label Extension Phase) (revised per Amendment 07)

The OLE Safety Analysis Set (OLE-SAS) is the group of subjects who receive at least 1 dose of 
study drug during the OLE Phase. 

The OLE Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 1 dose of 
study drug during the OLE Phase and have at least 1 postdose efficacy assessment during the 
OLE Phase.

The OLE PD Analysis Set is the group of subjects who have at least 1 posttreatment PD 
Page 234 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 21 of 164
measurement during the OLE Phase.
Efficacy and Biomarker Analyses (revised per Amendment 05)
Analysis for the Primary Endpoint (Core Study)
There is no primary efficacy endpoint.  (revised per Amendment 05)
Analysis for the Secondary Endpoints (Core Study)
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:
Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 18 months.  Data 
from early discontinuations will also be included.  (revised per Amendment 05)
Analysis for Exploratory Endpoints (Core Study)
(revised per Amendments 01, 02, 04, and 05)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) 
from 4 weeks and up to 18 months of treatment

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months
of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 months of 
treatment, and during posttreatment follow-up

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by vMRI 

Change from baseline in left and right hippocampal, whole brain, and total ventricular volume at 
6, 12, and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid levels
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, CBB, and 
FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
Pharmacokinetic Analyses (Core Study)
The PK Analysis Set will be used for elenbecestat (E2609) concentration listings and for summaries 
of elenbecestat (E2609) concentrations in plasma and CSF by dose and day. elenbecestat (E2609)
metabolite PK data may also be listed and summarized.  (revised per Amendment 05)
A population PK approach will be used to characterize the plasma PK of elenbecestat (E2609). For 
this approach, plasma PK data from this study will be pooled with relevant data from Phase 1 studies.  
As appropriate, the effect of covariates on the PK of elenbecestat (E2609) will be evaluated.  The PK 
model will be parameterized for oral clearance (CL/F) and apparent volume of distribution (Vz/F) for 
elenbecestat (E2609). Derived exposure parameters such as steady state area under the concentration 
time curve (AUCss) and average concentration (Cavg) of elenbecestat (E2609) and other derived 
parameters will be calculated from the model using the individual estimates parameterized for oral 
Page 235 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 22 of 164
clearance and dosing history. (revised per Amendment 04)
Pharmacodynamic Analyses (Core Study)
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma 
biomarkers, MRI endpoints).  The percentage change from baseline in CSF Aβ(1-x), Aβ(1-40), 
Aβ(1-42), t-tau, p-tau, and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months will be analyzed and presented graphically.  (revised per Amendments 04 and 05)  
Baseline levels and changes in t-tau and p-tau will be correlated with changes in CSF Aβ(1-42), 
imaging markers, and ApoE4 status.  Summary statistics for CSF biomarkers will be assessed for 
evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses (Core Study)
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI and 
elenbecestat (E2609) dose, plasma and CSF exposure will be initially explored graphically and any 
emergent relationship will be explored through population PK/PD modeling.  Additionally, the
relationship between CSF exposure to elenbecestat (E2609) and the change from baseline for 18 
months in the ADAS-cog, the CDR, and the MMSE will be explored graphically.  (revised per 
Amendments 04 and 05)
Additionally, the relationship between plasma exposures of elenbecestat (E2609) and select 
lymphocyte parameters will be explored graphically, and any emergent relationship will be explored 
using population-based modeling methods. (revised per Amendment 04)
Pharmacogenomic Analyses (Core Study)
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses (Core Study)
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, vital sign measurements, and cognitive decline 
assessment such as CBB will be summarized by treatment group using descriptive statistics.  (revised 
per Amendment 05)
Lymphocyte Subsets
Lymphocyte subsets, including but not limited to, CD4 [T helper cells], CD8 [cytotoxic T cells], 
CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells 
will be summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets 
and the mean change from baseline in lymphocyte subsets will also be displayed graphically over 
time by dose.  
Serum IgG, IgM, IgA will be measured and summarized in the same manner as other laboratory 
parameters. (revised per Amendment 04)
Interim Analyses Core Study
Page 236 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 23 of 164
In order to make decisions about the remainder of the study as well as the full elenbecestat (E2609)
clinical development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis 
and perform interim analyses of these data.  Investigators, other clinical site staff, subjects,  
caregivers/informants and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when 60 subjects (±20%) have completed 12 weeks 
of treatment (or discontinue study drug early).  (revised per Amendments 01, 03, 04, and 05) 
Stratification Core Study
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no).  (revised per Amendment 01)
Efficacy Analyses (Open-label Extension Phase)  (revised per Amendment 07)
The following secondary efficacy endpoints will be summarized by descriptive statistics and/or 
graphs, using OLE-FAS:

Changes from Core Study and OLE baselines in MMSE and FAQ scores

Changes from Core Study and OLE baselines in total hippocampal volume, left and right 
hippocampal volume, whole brain volume, and total ventricular volume at up to 24
months as measured by vMRI 
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis.
Pharmacodynamic Analyses (Open-label Extension Phase)  (revised per Amendment 07)
The OLE PD Analysis Set will be used for the summaries and analyses of PD biomarkers. The 
percentage change in plasma amyloid measurements from Core Study and OLE baselines to 12 and
24 months of OLE treatment will be analyzed and presented graphically.
Safety Analyses (Open-label Extension Phase) (revised per Amendment 07)
Safety analysis will be performed similarly to the Core Study. Evaluations of safety will be 
performed on the OLE Safety Analysis Set.  The incidence of AEs (including changes from baseline 
in physical and neurological examinations, and dermatological assessments), out-of-normal-range 
laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, suicidality 
(C-SSRS), and changes from baseline in laboratory safety test variables, ECGs, safety MRI, vital sign 
measurements, and cognitive decline assessment such as MMSE will be summarized by using 
descriptive statistics.  
Sample Size Rationale
A total of 15 subjects per dose is deemed sufficient to derive adequate safety and PK/PD data to aid 
in the selection of appropriate doses and the design of the Phase 3 studies that may be planned 
subsequently.  (revised per Amendment 04)  Based upon the selection of the elenbecestat (E2609)
50-mg dose for the Phase 3 studies, subjects randomized to the active treatment arms will be re-
assigned to the selected 50-mg dose for further evaluation. (revised per Amendment 06)
Page 237 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 24 of 164
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................29
5
ETHICS............................................................................................................................32
5.1
Institutional Review Boards/Independent Ethics Committees ..............................32
5.2
Ethical Conduct of the Study.................................................................................32
5.3
Subject Information and Informed Consent...........................................................33
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................35
7
INTRODUCTION ...........................................................................................................36
7.1
Results of Interim Evaluations...............................................................................37
7.2
Nonclinical and Clinical Safety Data.....................................................................37
8
STUDY OBJECTIVES....................................................................................................40
8.1
Primary Objective..................................................................................................40
8.2
Secondary Objectives.............................................................................................40
8.3
Exploratory Objectives ..........................................................................................40
9
INVESTIGATIONAL PLAN..........................................................................................42
9.1
Overall Study Design and Plan..............................................................................42
9.1.1
Prerandomization Phase...............................................................................44
9.1.1.1
Screening Period..................................................................................45
9.1.1.2
Baseline Period ....................................................................................47
9.1.2
Randomization Phase...................................................................................47
9.1.2.1
Treatment Period..................................................................................48
9.1.2.2
Early Discontinuation ..........................................................................48
9.1.2.3
Follow-Up Period.................................................................................48
9.1.3
Open-label Extension Phase ........................................................................48
9.1.3.1
Early Discontinuation ..........................................................................49
9.1.3.2
Follow-Up............................................................................................49
9.2
Discussion of Study Design, Including Choice of Control Groups.......................49
9.2.1
Overview......................................................................................................49
9.2.2
Rationale for Study Population....................................................................50
9.2.3
Rationale for Clinical Endpoints..................................................................51
9.2.4
Rationale for Biomarkers.............................................................................52
9.2.4.1
Overall Rationale .................................................................................52
9.2.4.2
Soluble Biomarkers in CSF .................................................................52
Page 238 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 25 of 164
9.2.4.3
Amyloid PET .......................................................................................53
9.2.4.4
vMRI....................................................................................................53
9.2.5
Clinical Risks and Mitigation Strategy........................................................54
9.3
Selection of Study Population................................................................................56
9.3.1
Inclusion Criteria .........................................................................................56
9.3.2
Exclusion Criteria ........................................................................................57
9.3.3
Removal of Subjects from Therapy or Assessment.....................................61
9.4
Treatments..............................................................................................................65
9.4.1
Treatments Administered.............................................................................65
9.4.2
Identity of Investigational Product...............................................................66
9.4.2.1
Chemical Name and Formula of Elenbecestat.....................................66
9.4.2.2
Comparator Drug .................................................................................66
9.4.2.3
Labeling for Study Drug......................................................................66
9.4.2.4
Storage Conditions...............................................................................67
9.4.3
Method of Assigning Subjects to Treatment Groups...................................67
9.4.4
Selection of Doses in the Study...................................................................67
9.4.5
Selection and Timing of Dose for Each Subject..........................................69
9.4.6
Blinding........................................................................................................69
9.4.7
Prior and Concomitant Therapy...................................................................70
9.4.8
Treatment Compliance.................................................................................72
9.4.9
Drug Supplies and Accountability...............................................................72
9.5
Study Assessments.................................................................................................74
9.5.1
Assessments.................................................................................................74
9.5.1.1
Demography.........................................................................................74
9.5.1.2
Baseline Assessments ..........................................................................74
9.5.1.2.1
Medical History and Physical Examinations.................................74
9.5.1.2.2
Viral Testing ..................................................................................74
9.5.1.2.3
B12 Testing....................................................................................74
9.5.1.2.4
TB Exposure Testing .....................................................................75
9.5.1.2.5
Urine Drug Testing ........................................................................75
9.5.1.3
Efficacy Assessments...........................................................................75
9.5.1.3.1
Psychometric Assessments ............................................................75
9.5.1.3.2
Volumetric MRI.............................................................................77
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................77
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................77
9.5.1.4.1
Pharmacokinetic Assessments .......................................................77
Page 239 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 26 of 164
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................78
9.5.1.5
Safety Assessments..............................................................................80
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..80
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................83
9.5.1.5.3
Laboratory Measurements .............................................................84
9.5.1.5.4
Vital Signs and Weight Measurements..........................................86
9.5.1.5.5
Physical Examinations...................................................................86
9.5.1.5.6
Electrocardiograms ........................................................................86
9.5.1.5.7
Safety MRI.....................................................................................87
9.5.1.5.8
Dermatologic Assessment..............................................................88
9.5.1.5.9
Neurologic Examination................................................................88
9.5.1.5.10
Pregnancy Test...............................................................................89
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................89
9.5.1.5.12
Biomarker Samples........................................................................89
9.5.1.5.13
Ophthalmic Examinations..............................................................89
9.5.2
Schedule of Procedures/Assessments ..........................................................89
9.5.2.1
Schedule of Procedures/Assessments ..................................................90
9.5.2.2
Description of Procedures/Assessments Schedule...............................98
9.5.3
Appropriateness of Measurements...............................................................99
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................99
9.5.4.1
Reporting of Serious Adverse Events..................................................99
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .....................................................................................100
9.5.4.3
Reporting of Events Associated with Special Situations...................101
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................101
9.5.4.3.2
Reporting of Study-Specific Events.............................................101
9.5.4.4
Expedited Reporting ..........................................................................101
9.5.4.5
Breaking the Blind.............................................................................102
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................102
9.5.5
Completion/Discontinuation of Subjects...................................................102
9.5.6
Abuse or Diversion of Study Drug ............................................................103
9.5.7
Confirmation of Medical Care by Another Physician ...............................103
9.6
Data Quality Assurance .......................................................................................103
9.6.1
Data Collection ..........................................................................................103
Page 240 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 27 of 164
9.6.2
Clinical Data Management ........................................................................104
9.7
Statistical Methods...............................................................................................104
9.7.1
Statistical and Analytical Plans..................................................................104
9.7.1.1
Study Endpoints.................................................................................104
9.7.1.1.1
Primary Endpoint.........................................................................104
9.7.1.1.2
Secondary Endpoints ...................................................................104
9.7.1.1.3
Exploratory Endpoints .................................................................105
9.7.1.2
Definitions of Analysis Sets...............................................................105
9.7.1.3
Subject Disposition............................................................................106
9.7.1.4
Demographic and Other Baseline Characteristics .............................106
9.7.1.5
Prior and Concomitant Therapy.........................................................106
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05) ......107
9.7.1.6.1
Primary Efficacy Analysis...........................................................107
9.7.1.6.2
Secondary Efficacy Analyses ......................................................107
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................107
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................108
9.7.1.7.1
Pharmacokinetic Analyses...........................................................108
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................108
9.7.1.8
Safety Analyses..................................................................................109
9.7.1.8.1
Extent of Exposure.......................................................................110
9.7.1.8.2
Adverse Events ............................................................................110
9.7.1.8.3
Laboratory Values........................................................................111
9.7.1.8.4
Vital Signs....................................................................................112
9.7.1.8.5
Electrocardiograms ......................................................................112
9.7.1.8.6
Other Safety Analyses..................................................................112
9.7.2
Determination of Sample Size ...................................................................113
9.7.3
Interim Analysis.........................................................................................113
9.7.4
Other Statistical/Analytical Issues .............................................................113
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................113
10
REFERENCE LIST .......................................................................................................114
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....118
11.1
Changes to the Protocol .......................................................................................118
11.2
Adherence to the Protocol....................................................................................118
11.3
Monitoring Procedures.........................................................................................118
11.4
Recording of Data................................................................................................119
11.5
Identification of Source Data...............................................................................119
Page 241 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 28 of 164
11.6
Retention of Records............................................................................................120
11.7
Auditing Procedures and Inspection....................................................................120
11.8
Handling of Study Drug.......................................................................................120
11.9
Publication of Results ..........................................................................................121
11.10 Disclosure and Confidentiality ............................................................................121
11.11 Discontinuation of Study .....................................................................................121
11.12 Subject Insurance and Indemnity.........................................................................122
12
APPENDICES ...............................................................................................................123
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................63
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................64
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................68
Table 4
Clinical Laboratory Tests...........................................................................85
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™..................................86
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................90
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................93
Table 8
Summary of Blood and CSF Sample Volumes..........................................98
LIST OF IN-TEXT FIGURES
Figure 1
Design of Core Study E2609-G000-202....................................................43
Figure 2
Assessments to be Performed at Screening by Tier...................................46
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................123
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........126
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 139
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................142
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................145
Appendix 6
Open-Label Extension Phase...................................................................149
Page 242 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 29 of 164
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg,
1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration × time curve 
AUC(0-24h)ss
area under the concentration × time curve at steady state from time zero to 
24 hours
AUCss
steady state area under the concentration × time curve
BACE1
Beta (β)-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
Cavg
average concentration
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carboxyesterase-2
CFR
Code of Federal Regulations
CL/F
oral clearance  
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
Page 243 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 30 of 164
Abbreviation
Term
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
Page 244 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 31 of 164
Abbreviation
Term
MMRM
mixed-effects model with repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OLE
Open-label Extension
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
pINN
proposed International Nonproprietary Name
PK
pharmacokinetic(s)
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
Randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
Tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
Unscheduled
vMRI
volumetric magnetic resonance imaging
Vz/F
apparent volume of distribution
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 245 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 32 of 164
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 246 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 33 of 164

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.  
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 247 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 34 of 164
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for from 4 weeks and up to 18 months 
(or at Early Discontinuation).  This consent for CSF sample collection is not required for 
study eligibility. (revised per Amendments 02 and 05)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects and will be via a 
separate, optional CSF consent form for the study.  (revised per Amendment 04)
Page 248 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 35 of 164
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 35 investigational sites in the United States.
(revised per 
Amendments 01, 02, 04, and 05)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 249 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 36 of 164
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010;
Lu, et al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, 
thus accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Rosen, et al., 1984; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
Elenbecestat (E2609) is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have 
shown that after oral dosing, elenbecestat (E2609) inhibits the production of Aβ40 and Aβ42 
in brain (rat and guinea pig) and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and 
monkey).
In humans, elenbecestat (E2609) has been shown to inhibit BACE1 enzyme 
activity in CSF and lower the levels of Aβ, including amyloid beta monomer from amino 
acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), in CSF both in vitro and in vivo.  See the 
Investigator’s Brochure for additional information.  The target indication for elenbecestat
(E2609) is therefore treatment and disease modification of AD.  
The present clinical study is a Phase 2 study for the elenbecestat (E2609) program, and is 
designed to establish safety in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol) and in subjects with mild to moderate AD.  (revised per Amendment 05)  This  
study will include a Core Study of approximately 32 months (including the Prerandomization 
and Randomization Phases) and an Open-label Extension (OLE) Phase of up to 27 months.
Page 250 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 37 of 164
(revised per Amendment 07)  Results from the Core Study will guide both the decision to 
move into Phase 3 development and the selection of the dose strengths to be taken into Phase 
3.  
In the MCI/Prodromal and mild to moderate AD population, the Core Study will compare 
placebo and 3 oral doses of elenbecestat (E2609) (5, 15, and 50 mg) administered once daily 
(QD) for 18 months.  (revised per Amendment 05)  
The
Core Study will include interim evaluations
of the pharmacokinetic (PK), 
pharmacodynamic (PD), safety, and tolerability of chronic dosing with elenbecestat (E2609). 
(revised per Amendment 05)  Furthermore, there will be close monitoring of safety by an 
independent data safety monitoring board (DSMB), including a formal safety review as soon 
as the randomized subjects (n=60, ±20%) have completed at least 12 weeks of treatment, 
have discontinued study drug or have withdrawn from the study.  (revised per Amendments
04 and 05) The study also includes a number of exclusion criteria, specific blinded safety 
monitoring procedures and safety criteria for discontinuation of study drug in light of the 
preclinical and clinical safety data collected to date following administration of elenbecestat
(E2609).  
The OLE Phase will evaluate the long-term safety and tolerability of elenbecestat (E2609); a 
detailed description of the OLE Phase is provided in Appendix 6. (revised per Amendment 
07)
7.1
Results of Interim Evaluations
(revised per Amendment 06)
Unblinded interim evaluations of the safety and tolerability of elenbecestat (E2609) 
suggested favorable safety at all doses of elenbecestat (E2609). Additionally, analyses of the 
PD effects (reduction from baseline in CSF Aβ levels) of elenbecestat (E2609) 5, 15, and 
50 mg per day have indicated that  elenbecestat (E2609) 50 mg per day produced relatively 
high levels of CSF Aβ reduction (greater than 50%). Based on the results of these analyses, 
elenbecestat (E2609) 50 mg per day has been selected as the dose for Phase 3 development. 
As elenbecestat (E2609) 5 and 15 mg per day will not be advanced clinically, subjects 
initially randomized to the elenbecestat (E2609) 5 and 15 mg per day treatment arms will be 
re-assigned in a blinded manner to the elenbecestat (E2609) 50 mg treatment arm provided 
that they will have at least 12 weeks of treatment remaining in the Randomization Phase. The 
purpose of this dose re-assignment is to further characterize the safety and tolerability of 
elenbecestat (E2609) 50 mg.  
7.2
Nonclinical and Clinical Safety Data
The toxicity of elenbecestat (E2609) has been evaluated in oral repeated-dose toxicology 
studies of up to 26 weeks duration in rats and 39 weeks in cynomologus monkeys.  
Nonclinical findings of note include immunologic-related findings at 30 mg/kg and above in 
monkeys (including 1 cytomegalovirus-related death at 60 mg/kg).  An additional completed 
Page 251 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 38 of 164
monkey immunology study suggested that lymphocytes and lymphocyte subsets may be 
suitable markers to monitor potential immunotoxicity or immunomodulation by elenbecestat
(E2609) in a clinical setting.  Further details of the nonclinical data to date with elenbecestat
(E2609) can be found in the Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the PK levels of elenbecestat (E2609) and the PD effects on 
BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of elenbecestat (E2609).  It also investigated the effects of elenbecestat
(E2609) on the PK properties of digoxin. The clinical phase has been completed and 
reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]-elenbecestat (E2609) in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of elenbecestat (E2609) under 
fasted conditions and a tablet formulation administered under fed and fasted conditions in 
healthy subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with elenbecestat (E2609).   The clinical safety data 
are described in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with elenbecestat
(E2609).  In elderly subjects treated with 50 mg of elenbecestat (E2609), tolerability was 
comparable to younger subjects.  There were no specific AEs in elderly subjects which were 
evidently more frequent than in younger subjects.  No serious adverse events (SAEs) were 
reported, and there were no clinically significant changes in mean laboratory safety 
parameters, vital signs, or electrocardiogram (ECG) parameters.  The 800 mg (maximum) 
Page 252 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 39 of 164
dose was associated with a small increase of QTc interval calculated using Fridericia’s 
formula (QTcF) from baseline (14.9 msec at 4 hours postdose), consistent with nonclinical 
findings.  Overall the data suggested that a single dose of elenbecestat (E2609) might reduce 
some lymphocyte subsets (eg, CD4 [T helper cells], CD8 [cytotoxic T cells]) but the effects 
were highly variable across doses and the findings were not conclusive.  There were no 
trends to suggest that elenbecestat (E2609) altered immunoglobulin (Ig) levels. There were 
no clinical manifestations in terms of primary infections or relapse of latent infections in 
subjects who received single doses of elenbecestat (E2609).  A single dose of elenbecestat
(E2609) up to 800 mg is not considered to pose clinical safety concerns with regard to 
immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, elenbecestat (E2609) administered at doses of 200 and 400 mg was 
associated with reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B 
cells) counts at Day 8.  These reductions were more clearly evident by Day 15, consistent 
with a treatment by time interaction in the statistical analysis.  There was evidence that the 
lower doses of 50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 
15.  Doses above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
elenbecestat (E2609) on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 
200 and 400 mg to a level close to or less than the lower limit of normal (LLN) could be 
associated with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of elenbecestat
(E2609).  Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of elenbecestat (E2609).  Therefore, no restrictions are required for the use of 
concomitant medications which are known to be inducers of CYP450 enzymes.  Donepezil (a 
moderate CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of 
elenbecestat (E2609) when coadministered with elenbecestat (E2609) but not when dosed at 
least 2 hours apart from elenbecestat (E2609). Elenbecestat (E2609) (which inhibits the 
P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  Nonclinical studies 
also indicated that other CYP pathways apart from CYP3A4 would not be major pathways of 
metabolism of elenbecestat (E2609). 
Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 253 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 40 of 164
8
STUDY OBJECTIVES
Objectives for the OLE Phase are provided in Appendix 6. (revised per Amendment 07)
8.1
Primary Objective
(revised per Amendment 05)
The primary objective is:  

To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with elenbecestat (E2609) in MCI/Prodromal subjects and in 
subjects with mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendments 02 and 05)

To characterize the plasma and CSF PK of elenbecestat

To assess the effects of elenbecestat on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and
at 18 months of treatment 
8.3
Exploratory Objectives
(revised per Amendments 01,02, 04, and 05)  
The exploratory objectives are:  
To explore the effects of elenbecestat (E2609) compared on CSF Aβ(1-40) and BACE1 
measurements from 4 weeks and up to 18 months of treatment 
To explore the effects of elenbecestat (E2609) compared with placebo on various 
biomarkers.  Biomarkers to be explored may include, but not limited to:  
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
To explore the effects of elenbecestat (E2609) compared with placebo on clinical status 
at various time points during 18 months of treatment, and during posttreatment follow-up
by assessment of:  
Page 254 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 41 of 164
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
To explore the relationship between the treatment effects of elenbecestat (E2609) on 
measured clinical efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF 
amyloid isoforms, brain amyloid, and vMRI 
To explore relationships between both elenbecestat (E2609) dose and exposure, with PD 
and safety endpoints 
Page 255 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 42 of 164
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study with an OLE Phase of up to 27 months in subjects with MCI/Prodromal 
AD or mild to moderate AD.  (revised per Amendments 01 and 07)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists of 3 phases: 
Prerandomization, Randomization, and OLE.  The 
Prerandomization and Randomization Phases are referred to as the Core Study throughout the 
protocol.  (revised per Amendment 07).  
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
All subjects (MCI/Prodromal and mild to moderate AD) will initially be randomized 1:1:1:1 
to 4 treatment groups (5, 15, or 50 mg elenbecestat [E2609] or placebo) (revised per 
Amendments 01 and 05).  Upon implementation of Amendment 06, at the next regularly 
scheduled visit, subjects receiving elenbecestat (E2609) 5 or 15 mg who have not yet 
completed Visit 17 (Week 66), will be re-assigned in a blinded manner to elenbecestat
(E2609) 50 mg for the remainder of the treatment period.  In order to maintain the blind, all 
subjects who have not yet had Visit 17 will go through the same procedures with the 
placebo-randomized subjects continuing to receive placebo and those randomized to 
elenbecestat (E2609) 50 mg continuing to receive 50 mg.  (revised per Amendment 06)
All subjects who complete 18 months of treatment and 12 weeks of follow-up in the Core 
Study and who satisfy the entry criteria for the OLE Phase are eligible to enter the OLE 
Phase.  During the OLE Phase, subjects will receive elenbecestat (E2609) 50 mg daily for up 
to 24 months (2 years).
Page 256 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 43 of 164
An overview of the Core Study design is presented in Figure 1.
Figure 1
Design of Core Study E2609-G000-202
(revised per Amendments 01, 02, 05, and 06)
R = randomization, AD = Alzheimer’s Disease, MCI = mild cognitive impairment.
This study will be limited to approximately 35 sites in the United States, with approximately 
60 (±20%) eligible subjects randomized at Visit 3, 1:1:1:1 to 4 treatment groups within each 
clinical cohort.  In addition to the placebo group, 3 doses of elenbecestat (E2609) will be
used to reduce CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg)
from baseline, respectively, at steady state.  PK/PD modeling shows these doses should 
achieve these targets when administered QD with food and will be evaluated based on the 
4-week (or later) assessment of CSF Aβ(1-x) from subjects who provide voluntary consent 
for CSF measurement (see Section 9.4.4 ). (revised per Amendments 01, 02, 04, and 05)
Safety data will be monitored in a blinded fashion on a regular basis.  
In addition, approximately every 3 months from the time the 1st subject is randomized into
the study through the time the last subject is randomized, an independent DSMB (including 
at least 1 immunologist) will review all safety data in an unblinded manner. (revised per 
amendment 06) The DSMB will make recommendations to Eisai after each review as to 
whether any change(s) to the study are necessary.  (revised per Amendments 01, 04, and 05)  
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
Page 257 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 44 of 164
Interim analyses of the elenbecestat (E2609) plasma PK for all subjects and the elenbecestat
(E2609) CSF PK and PD profiles will be performed on baseline data and samples collected 
after at least 4 weeks of treatment in the Core Study.  (revised per Amendment 05 and 07)  
Refer Section 9.7.3 for more detail.  These data will be used to evaluate the CSF PD effects 
of elenbecestat (E2609) doses, where PD is measured as reductions from baseline in CSF 
Aβ(1-x) levels (see Section 9.4.4). The median and mean percentage change from baseline 
in CSF Aβ(1-x) measured after 4 weeks or more of treatment for each dose of elenbecestat
(E2609) and the 90% confidence interval (CI) for the median will be derived.  In addition, 
exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the observed 
PK and PD data and will relate the average steady state plasma concentration of elenbecestat
(E2609) to steady state CSF Aβ(1-x) percentage reduction from baseline determined after at 
least 4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)
Once subjects have completed at least 12 weeks of treatment in the Core Study (or 
discontinued study drug early), an interim safety analysis will be conducted by Eisai and the 
DSMB.  (revised per Amendments 01, 04, and 05)  At the completion of this interim safety 
review, the frequency of subsequent unblinded safety reviews will be re-evaluated by the 
DSMB and the Sponsor and this information will be provided in the DSMB charter. (revised 
per Amendment 06) Subjects will continue study drug while the DSMB reviews all the 
available safety data.  (revised per Amendment 05)  At the time of this interim safety 
analysis, some subjects will have more than 12 weeks of safety data.  
Interim analyses are planned and are discussed in Section
9.7.3.
(revised per 
Amendment 03)
Based on the results of the interim analyses, the elenbecestat (E2609) 50 mg dose has been 
chosen as the clinical dose for the Phase 3 studies.  In order to collect additional safety data 
for elenbecestat (E2609) 50 mg, subjects randomized to elenbecestat (E2609) 5 or 15 mg in 
this study will be re-assigned to elenbecestat (E2609) 50 mg if and only if these subjects have 
at least 12 weeks of treatment remaining in the Randomization Phase following study drug 
dose re-assignment.  Therefore, subjects who completed Visit 17 assessments prior to the 
implementation of Amendment 06 will remain on their original randomized dose.  As study 
drug dose re-assignment will occur in a blinded manner, a 4-week interim safety assessment 
following study drug re-assignment will be required for all subjects.  (revised per 
Amendment 06)
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
Page 258 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 45 of 164
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during
this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization, the clinician will provide a judgment on the classification of a subject as 
either MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This 
judgment may be discussed and reviewed with the Sponsor or Sponsor’s representative, as 
necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
Page 259 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 46 of 164
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 260 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 47 of 164
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination (including 
the Brief Smell Identification Test [Sensonics Inc.]) will be performed.  (revised per 
Amendment 04) A urine pregnancy test will be conducted for females of childbearing 
potential.  Blood will be collected from all subjects for clinical chemistry and hematology, 
lymphocyte subset analyses, Ig analyses, and PD assessments.  Blood samples will be 
collected and stored for determination of a subject’s previous exposure to infective pathogens 
in the event of AEs that warrant further investigation occurring at a later point in the study.  
Psychometric assessments will be administered to the subject in the order stated in Table 6.  
The caregiver or informant needs to be present at this visit.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, a CSF sample will be obtained at this 
visit for PK and PD assessments (see Section 9.5.1.4).  (revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the N-acetyltransferase 2 (NAT2) phenotype of subjects 
enrolled in the study (see Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-up Period of 12 weeks after the last dose of study drug.  
Page 261 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 48 of 164
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  (revised per Amendment 06)
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug.  (revised 
per Amendments 04 and 05)  
9.1.2.3
Follow-up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 4 posttreatment Follow-Up Visits: 2, 4, 8, and 
12 weeks after the last dose of study drug.  If clinically indicated, more frequent safety 
assessments can be conducted as part of unscheduled visits during the posttreatment 
Follow-up Period. (revised per Amendment 04)
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Apr 2018.  (revised 
per Amendment 05)

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.1.3
Open-label Extension Phase
A complete description of the OLE Phase is provided in Appendix 6; key features are 
summarized below. (revised per Amendment 07)
After completing all Visit 20 follow-up procedures for the Core Study, eligible subjects will 
have the option to participate in the OLE Phase within 4 weeks of Core Study Visit 20.  
These subjects may transition to the OLE Phase immediately following Visit 20 (on the same 
day) if the decision to proceed with the OLE Phase has been made at that time.  The Medical 
Monitor must be contacted if Visit 21 (start of the OLE Phase) is to occur more than 4 weeks 
after Visit 20.  
Page 262 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 49 of 164
For all subjects, assessments performed at Visit 20 may serve as the Visit 21 (start of the 
OLE Phase) results with the following exceptions: laboratory assessments and vital signs 
must be repeated if Visit 21 occurs more than 10 days after Visit 20.
Subjects who are eligible and who consent to participate in the OLE Phase will be 
administered elenbecestat (E2609) 50 mg daily at Visit 21.  Subjects with pending INR and 
serum pregnancy test results (females subjects of child bearing potential only) but who are 
otherwise qualified may begin OLE dosing at Visit 21; however, these subjects must 
discontinue study drug immediately if either test result meets the exclusion criteria.
During the OLE Phase, safety assessments will continue to be monitored and all AEs and 
SAEs will be recorded.  Vital signs, hematology, blood chemistry, and urine values will be 
monitored at every scheduled visit. Clinical assessments (MMSE and FAQ) will be 
administered every 3 months.  Blood for PD analyses will collected after 12 and 24 of OLE 
treatment. All subjects will be assessed using safety MRIs and vMRI measurements at the 
end of the OLE Phase.
9.1.3.1
Early Discontinuation
Subjects who prematurely discontinue study drug for any reason will undergo an ED Visit 
within 7 days of their last dose of study drug.  Follow-Up Visits will also be scheduled 4 and 
12 weeks after the last dose of study drug.  
9.1.3.2
Follow-Up 
All subjects, regardless of whether they complete all 24 months of treatment in the OLE 
Phase or prematurely discontinue study drug will complete 2 posttreatment Follow-Up Visits 
at 4 and 12 weeks after the last dose of study drug. If clinically indicated, more frequent 
safety assessments can be conducted as part of Unscheduled Visits during the OLE Follow-
up Period. 
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The primary objective of the study is to assess the safety and tolerability of daily dosing with 
elenbecestat (E2609) in subjects with MCI/Prodromal AD and in subjects with mild to 
moderate AD. Immunological and hematological parameters will also be assessed.  (revised 
per Amendment 04)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
Page 263 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 50 of 164
Secondary endpoints include CSF PK and plasma PK parameters of elenbecestat (E2609) 
based on population PK analysis and the percentage reduction of Aβ(1-x) and Aβ(1-42) in 
CSF relative to baseline from 4 weeks and up to 18 months of treatment. The intrinsic and 
extrinsic factors on the PK characteristics will also be explored.
Exploratory endpoints include CSF Aβ(1-40) and BACE1 measures as well as CSF 
biomarkers of neuronal degeneration (eg, t-tau and p-tau), volumetric MRI measurements, 
plasma amyloid measurements, brain amyloid levels as measured by amyloid PET and 
clinical assessments.  (revised per Amendment 05) Exploratory endpoints including 
assessments of efficacy, safety, and other biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups (Section 9.7.4)  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means elenbecestat (E2609) is more likely to be 
efficacious (ie, slow disease progression) the earlier in disease progression treatment is 
started, where limited neurodegeneration has occurred and associated clinical deficits are at a 
minimum.  However, since the effect of BACE1 inhibition along the AD continuum remains 
to be characterized, elenbecestat (E2609) will also be evaluated for its profile in mild to 
moderate stages of AD, in the event data emerge supporting its use beyond MCI/Prodromal 
AD. Indeed, recent data support the notion of continued progression of amyloid pathology 
even in these later stages of the disease (Hu, et al., 2015), although at a slower pace, 
suggesting a positive effect of BACE inhibition and amyloid beta reduction cannot be ruled 
out even in the later stages of the disease trajectory.  Hence, in this study, elenbecestat
(E2609) will be assessed in subjects with disease states ranging from MCI/Prodromal to mild 
and even moderate AD.  (revised per Amendment 01)  
Page 264 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 51 of 164
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as elenbecestat (E2609) in subjects with more advanced 
disease such as mild to moderate AD.  (revised per Amendment 01)  For example, a study of 
tarenflurbil, a selective Aβ(1-42)-lowering agent, on cognition and function in subjects with 
mild to moderate AD showed the subjects with mild AD had lower rates of decline than those 
in the placebo group in activities of daily living and global function; however, slowing of 
cognitive decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential 
effects on cognitive measures have been observed with solanezumab, where some benefit 
from treatment was observed in subjects with mild AD, although studies with solanezumab 
were considered to have failed to improve cognition or functional ability significantly 
(Doody, et al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor 
elenbecestat (E2609) in 2 different subject populations that differ in terms of AD severity
before the initiation of large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for Clinical Endpoints
The 14-item version of the ADAS-Cog will be used in the present study since it is considered 
more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975)
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable 
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with elenbecestat (E2609) treatment. 
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
Page 265 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 52 of 164
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living.  The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  Volumetric magnetic resonance imaging is discussed in 
Section 9.2.4.4.
9.2.4
Rationale for Biomarkers
9.2.4.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (t-tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.4.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of elenbecestat (E2609) 
on Aβ(1-40) +Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) 
through inhibition of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both t-tau and p-tau are sensitive markers of axonal and neuronal degeneration (t-tau) and 
neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel with 
disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have been 
Page 266 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 53 of 164
correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful predictors 
of cognitive decline and progression to dementia due to AD.  Rebalancing dysregulated 
amyloid production early in the process may positively affect the neurodegenerative process 
and thus affect these markers and benefit the disease trajectory.  Therefore, monitoring these 
markers in conjunction with amyloid imaging may provide further supportive evidence of 
disease modifying effects.  (revised per Amendment 04)
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.4.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of elenbecestat (E2609) on 
amyloid levels in the brain, both by whole brain analysis (the average of 5 to 6 cortical
regions) and brain region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment in the 
Core Study (or at ED, providing the subject has received at least 39 weeks of study drug) as 
an exploratory measure of the potential disease-modifying effects of elenbecestat (E2609). 
(revised per Amendment 07) Longitudinal amyloid PET imaging will only be conducted on 
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses). (Revised per Amendments 02 and 05)
9.2.4.4
vMRI
Volumetric imaging will be used to evaluate the effects of elenbecestat (E2609) on rates of 
atrophy across the different dose groups during the Core Study and to provide support that 
effective treatment is associated with modification of disease course (exploratory endpoints
in the Core Study and OLE Phase).  (revised per Amendments 01 and 07) A large body of 
data has shown that structural MRI reliably tracks disease progression in AD.  Atrophy tends 
to occur preferentially in the lateral temporal and posterior parietal regions during the early 
stages of disease and progresses towards the anterior regions of the brain (frontal cortex) in 
its later stages.  Clinically efficacious doses are predicted to be associated with a slowing in 
the rate of hippocampal atrophy compared with rates observed in the placebo and non-
efficacious dose groups.  Treatment effects on left and right hippocampal, whole brain, and
total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
Page 267 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 54 of 164
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/mL or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF t-tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals during the Core Study and at the end of the OLE Phase, these 
relationships and the effects of elenbecestat (E2609) treatment will be explored further.  
(revised per Amendment 07) Recent advances in analysis software have made structural 
imaging more sensitive to detect small changes and able to reliably measure rates of atrophy 
at these intervals, particularly in the posterior parietal and the lateral temporal regions during 
the early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.5
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the
preclinical and clinical safety data with elenbecestat (E2609), and to mitigate clinical risk in 
the progression from 14 days of dosing in the MAD study to 18 months of Core Study 
treatment and 24 months of OLE Phase treatment in this Phase 2 study.
(revised per 
Amendment 07)  These safety aspects include the following:  

Immunology-related and infection-related exclusion criteria for both the Core Study and 
the OLE Phase (revised per Amendment 07)

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for study drug discontinuation based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) during the Core Study and absolute lymphocytes
during the OLE Phase (revised per Amendment 07)

Safety criteria for study drug discontinuation during the Core Study and OLE Phase 
based on skin rash, reoccurrence of herpes virus infections including any oral herpes, 
genital herpes or shingles, other infections, MRI changes, ECGs, and pregnancy.
(revised per Amendment 07)
Page 268 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 55 of 164
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and dermatological 
assessments at regular intervals. (revised per Amendment 07) AEs that might indicate 
signals of possible drug abuse potential will require a detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned 
on the frequency and impact of these events.  To assess potential immunomodulatory 
effects, peripheral blood mononuclear cells (PBMCs) will be collected at baseline, during 
treatment, and posttreatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with elenbecestat 
(E2609) to date, assessments using standardized photography will be performed by a central 
reviewing dermatologist at regular intervals during the Core Study. During the OLE Phase,  a 
dermatologic assessment will be performed by the investigator at every scheduled visit.  
Every assessment will specifically include evaluation of any areas of depigmentation or any 
rash. (revised per Amendment 07) Dermatological assessments will be supplemented with a 
specific question to subjects regarding skin changes at each visit.  Any such changes could be 
referred to the central reviewing dermatologist, and to a local dermatologist if needed, for 
further evaluation.  See Section 9.5.1.5.8 and Appendix 6 for further details. (revised per 
Amendment 07)

Baseline and on-study blood will be taken and stored for all subjects during the Core 
Study and OLE Phase.  (revised per Amendment 02 and 07) DNA samples and CSF 
samples (for all subjects who consent to CSF sample collection) will be taken and stored 
during the Core Study. (revised per Amendment 02 and 07)  These samples may be tested 
in the event that a subject develops AEs that warrant further investigation (eg, if a subject 
develops a treatment-emergent infection) (see Section 9.5.1.2.2 and Appendix 6).
(revised per Amendment 07)

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Core Study Treatment Period, and at the final Follow-Up Visit during the Core 
Study.  (revised per Amendment 07) MRI assessments will also be performed at the end 
of the OLE Treatment Period.  In addition, safety brain MRI assessments may be 
performed as an unscheduled assessment if clinically indicated.  (revised per Amendment 
07)

Full neurologic examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  Details of the neurologic
examination are given in Section 9.5.1.5.9 and Appendix 6. (revised per Amendment 07)
Page 269 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 56 of 164

Cognitive decline will be assessed as a safety assessment during the Core Study
(ADAS-cog14, MMSE, and CBB) and during the OLE Phase (MMSE). (revised per 
Amendment 07) Of particular importance will be the assessment of reaction time testing 
using the detection and identification tasks on the CBB during the Core Study. (revised 
per Amendment 07)

During the Core Study, an assessment of suicidality using the C-SSRS will be performed 
at Screening, Baseline, and at regular intervals during the Treatment and Follow-up
Period (see Section 9.5.1.5.11). During the OLE Phase, C-SSRS will be performed at 
Visit 21 (start of OLE treatment) and Visit 32 or the ED Visit (end of OLE treatment). 
Additional clinical assessments of reported suicidal thinking and behavior will be 
performed by the investigator at every scheduled visit during the OLE Phase (see 
Appendix 6). (revised per Amendment 07)

All subjects, regardless of whether they complete all 18 months of treatment or 
prematurely discontinue study drug during the Core Study, will have at least 4 off-
treatment Follow-Up Visits during the Core Study (2, 4, 8, and 12 weeks after the last 
dose of study drug). Subjects who complete or prematurely discontinue study drug 
during the OLE Phase will have 2 off-treatment Follow-Up Visits at 4 and 12 weeks after 
the last dose of study drug. (revised per Amendment 07)

More frequent safety assessments can be made as unscheduled assessments/visits during 
the off-treatment Follow-Up period, if clinically indicated. (revised per Amendment 04)

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the Core Study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Approximately 60 (±20%) eligible MCI/Prodromal or mild to moderate AD subjects will be 
randomized at approximately 35 sites in the United States (revised per Amendments 02 and 
04).  There will be no restriction to the number of subjects from either population.  
Subjects who do not meet all of the inclusion criteria in Section 9.3.1 or who meet any of the 
exclusion criteria in Section 9.3.2 will not be eligible to receive study drug during the Core 
Study.
Subjects who do not meet all of the inclusion criteria or who meet any of the 
exclusion criteria provided in Appendix 6 will not be eligible to enter the OLE Phase. 
(revised per Amendment 07) 
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)
Required at Screening Visit 1:
Page 270 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 57 of 164
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Page 271 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 58 of 164
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
Page 272 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 59 of 164
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
Page 273 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 60 of 164
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
Page 274 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 61 of 164
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.

(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).  (revised per Amendment 04)
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Page 275 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 62 of 164
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug in the Core 
Study (see Section 9.1.2.3), and 4 and 12 weeks after the last dose of study drug in the OLE 
Phase (see Appendix 6). (revised per Amendments 04, 05 and 07)
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug during the Core Study include the 
following: (revised per Amendments 07)
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test but who 
has no clinical signs or symptoms of infection, will have study drug temporarily 
suspended for at least 2 weeks but no more than 4 weeks.  During this period of study
drug suspension, lymphocyte subset counts and complete blood count (CBC) with 
differentials will continue to be tested weekly until CD4 (T helper cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) have all returned to greater than the population-adjusted
LLN after which time study drug can be resumed.  Testing of lymphocyte subset counts 
and CBC with differentials is required weekly for 4 weeks following resumption of study 
drug administration.  Temporary suspension and rechallenge with study drug is only
permitted once for any given subject.  If the lymphocytes and CD counts do not return to 
greater than the population-adjusted LLN within 4 weeks from the start of temporary 
suspension the subject will need to be permanently discontinued from study drug.  
(revised per Amendment 04)
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendments 02 
and 04)  During the early stages of the treatment period, where visits are conducted 
weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already scheduled to be 
measured on a weekly basis and so additional visits or blood draws are not required.  
(revised per Amendment 02)  For these subjects, the decision as to whether the subject 
remains on study drug or is to be discontinued from study drug will be based upon 
clinical judgment and will take into account any clinical presentation in addition to the 
Page 276 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 63 of 164
lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue, 
discontinue, or temporarily 
suspend study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts below 
discontinuation threshold and no clinical signs 
or symptoms of infection
Retest within 1 week along 
with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
temporarily suspend study 
drug for between 2 and 
4 weeks.  Continue weekly 
testing of lymphocyte subsets 
and CBC with differentials.  
Rechallenge with study drug 
allowed when CD4 (T helper 
cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) 
absolute counts all greater 
than population-adjusted 
LLN.  Temporary suspension 
and rechallenge permitted 
only once for each subject.
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold
Lymphocyte subset counts 
(and CBC with differentials) 
to be performed weekly until 
lymphocyte subset counts 
return to ≥ population-
adjusted LLN 
Decision will be based upon 
lymphocyte subset counts 
and clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  
(Table revised per Amendments 02 and 04)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
Page 277 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 64 of 164
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds, subjects with infections of moderate intensity will be 
discontinued from study drug (eg, subjects whose infections are not localized, or subjects 
who are systemically unwell, or who require systemic anti-infective drug treatment).   All 
subjects with infection who are discontinued from study drug will be followed for a 
period of 12 weeks or until the infection resolves/ stabilizes or until the CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have returned to 
greater than population-adjusted LLN (whichever comes latest).
(revised per 
Amendments 02 and 04)
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts below 
discontinuation threshold
If confirmed with 
repeat testing within 
1 week, then 
temporarily suspend 
study drug as per 
instructions above.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts between 
population-adjusted LLN and 
discontinuation threshold 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts always >
population-adjusted LLN 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  
(Table revised per Amendments 02 and 04)
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
Page 278 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 65 of 164
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 2, 4, 8, and 12 weeks after the last 
dose of study drug.  They will also undertake an Unscheduled Visit (with MRI) at 
approximately 4 weeks after the visit at which such MRI features were first identified.  
An MRI will also be performed at approximately the time of the final Follow-Up Visit
(Visit 20).  Additional visits for safety may be arranged if clinically indicated in the 
opinion of the investigator, including after 12 weeks after the last dose of study drug.  At 
any time during the treatment period, subjects who have asymptomatic, treatment-
emergent microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
(revised per Amendment 04)
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
Safety-related criteria for discontinuation of study drug during the OLE Phase are provided 
in Appendix 6. (revised per Amendment 07)
9.4
Treatments
9.4.1
Treatments Administered
For the Core Study, the test drug is elenbecestat (E2609) and the control drug is placebo. 
(revised per Amendments 07) All study drugs are to be administered orally, QD, with food.  
Treatments to be administered during the Core Study are 5, 15, and 50 mg elenbecestat 
(E2609) or placebo prior to the implementation of Amendment 06, and 50 mg elenbecestat
(E2609) or placebo after the implementation of Amendment 06 as shown in Figure 1.  
(revised per Amendments 01, 05, 06, and 07)  Study treatment will begin on Day 1 (at the 
study site) following Randomization and will continue for approximately 78 weeks.  Please 
refer to Table 7 and Section 9.5.1.4.1 for specific information on drug administration on days 
when PK sampling is to be performed.
Page 279 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 66 of 164
Treatments to be administered during the OLE Phase are described in Appendix 6. (revised 
per Amendment 07)
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
Elenbecestat (E2609) tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo 
tablets of identical appearance will also be available. Each subject will receive 2 tablets, 
which combined will make up the required doses of elenbecestat (E2609) 5, 15, 50 mg, or 
placebo.  The tablets will be supplied by the Sponsor in labeled blister packs.  The product 
release certificates for elenbecestat (E2609) and placebo will be included in the clinical study 
report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either elenbecestat (E2609) or placebo, or both (see 
Section 9.4.2.3 for labeling details).
9.4.2.1
Chemical Name and Formula of Elenbecestat (E2609)

Test drug code:  
E2609

Generic name:  
Elenbecestat (pINN)

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula: 
C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Elenbecestat (E2609) will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.  The following information may be included but is not limited to:  
Page 280 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 67 of 164

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups are 
described in Section 9.4.1. (revised per Amendments 01 and 05)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, initial doses will be selected such that at steady state, they will result 
in 25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of 
PD effects.  (revised per Amendment 06)
In Study 007, the relative bioavailability of a tablet formulation of elenbecestat (E2609) in 
the fed and the fasted states compared with the capsule formulation in the fasted state (used 
in Studies 001 and 002) was investigated.
It was found that when the tablet form of 
elenbecestat (E2609) (50 mg) was administered with food, the exposure (ie, AUC) of the
parent drug elenbecestat was higher, with lower maximum observed concentrations and 
reduced exposure to the metabolites, compared with either formulation in the fasted state.
Page 281 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 68 of 164
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study 
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
Elenbecestat (E2609) 
Tablet Daily Dose (mg) 
With Food
Plasma Elenbecestat (E2609)
% Reduction CSF 
BACE1 Activity
% Reduction 
CSF A(1-x)
Cmax,ss
(ng/mL)
Css,av
(ng/mL)
AUC(0-24h)ss
(ng·h/mL)
5 
6.2
3.3
80.3
16.2
33
15 
18.6
10
240.9
36.6
56
50 
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = beta-amyloid converting enzyme, CSF = cerebrospinal fluid, Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from 
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1 
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of elenbecestat (E2609) 
effects in healthy subjects will be applicable for both MCI/Prodromal and mild to moderate 
AD dementia patients.  (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on elenbecestat (E2609) 
decreased by 3.1% from baseline, whereas the placebo control showed an increase of 8.7%), 
but this decrease was less than that observed at doses of 200 mg (22.9% decrease) or 
400 mg (17.3% decrease).  No subject had infections or drug rash while receiving 
elenbecestat (E2609) 100 mg QD or at lower doses in Study 002, whereas at 200 and 400 mg 
QD, 4 subjects had symptomatic orolabial HSV1 relapses and 2 subjects at the highest dose 
had drug rash.  The highest dose for Study 202 of 50 mg QD (tablet administered with food) 
is therefore expected to have a similar or better safety profile compared with the 100 mg QD 
capsule (administered fasted) in Study 002.  Specific exclusion criteria, blinded and 
unblinded safety monitoring procedures, and safety criteria for discontinuation from study 
drug are included in this study in order to mitigate any immunology-related risk with 
elenbecestat (E2609), particularly in light of the progression from 14 days of dosing 
(Study 002) to 18 months of dosing in this study.
Page 282 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 69 of 164
Interim analyses of the elenbecestat (E2609) plasma PK for all subjects and the elenbecestat
(E2609) CSF PK and PD profiles will be performed on baseline data and samples collected 
after at least 4 weeks of treatment.  These interim analyses, as well as analyses of safety data, 
will be performed on an ongoing basis.  Refer Section 9.7.3 for more detail. The median and 
mean percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment 
for each dose of elenbecestat (E2609) and its 90% confidence interval for the median will be 
derived.  In addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling 
will use the observed PK and PD data and will relate the average steady state plasma 
concentration of elenbecestat (E2609) to steady state CSF Aβ(1-x) percentage reduction from 
baseline after at least 4 weeks of dosing.  (revised per Amendments 01, 02, 03, 04, and 05)
Unblinded interim analyses have indicated elenbecestat (E2609) 50 mg per day produced 
relatively high levels of CSF Aβ reduction (greater than 50%) with an acceptable safety 
profile.  As a result, elenbecestat (E2609) 50 mg has been selected as the dose for Phase 3 
development.  To gain a more comprehensive safety and tolerability profile of elenbecestat 
(E2609) 50 mg, subjects randomized to elenbecestat (E2609) 5 and 15 mg will be re-assigned 
to elenbecestat (E2609) 50 mg for the remaining of the 18-month treatment period with the 
provision that they will have at least 12 weeks of treatment remaining in the Randomization 
Phase.  (revised per Amendment 06)
9.4.5
Selection and Timing of Dose for Each Subject
Elenbecestat (E2609) is administered orally, QD, with food.  Study treatment will begin on 
Day 1 following randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
Elenbecestat (E2609) and placebo will be administered as tablets of identical appearance
during the Core Study.  
During the Randomization Phase and Follow-Up Phase in the Core Study, subjects,
caregivers/informants, and all clinical site personnel involved with the conduct and 
interpretation of the study, including investigators will be blinded to the treatment codes
(double-blind).  In order to make decisions about the remainder of the study as well as the 
full elenbecestat (E2609) clinical development program, the sponsor will unblind safety, PK, 
and PD data on an ongoing basis and perform interim analyses of these data.  (revised per 
Amendment 03)
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Page 283 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 70 of 164
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.
The PK/PD interim analyses will take place throughout the study as per Amendment 03 and 
will be conducted by an independent PK/PD scientist at the sponsor.  Any additional changes 
to dose required for this study will be reflected in a further amendment to the protocol and 
the Statistical Analysis Plan will detail how data will be handled in the primary analysis. 
(revised per Amendments 02 and 04)
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs during the Core Study and OLE Phase are 
provided in Appendix 2. (revised per Amendment 07) Prohibited medications are presented 
in Listing 1 through Listing 5.  Medications that are permitted with restrictions are listed in
Listing 6 through Listing 8. (revised per Amendment 04)
The types of agents listed below are not permitted before randomization unless discontinued 
according to the specific timeframes as shown below; these types of agents are not permitted 
during the Core Study or OLE Phase until after the last treatment visit:  (revised per 
Amendments 04 and 07)

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines
Page 284 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 71 of 164

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization.  However,
during the treatment period of the study, short term (not more than 14 days) use of 
steroids up to the equivalent of prednisolone 40 mg once daily is permitted after 
discussion with the Medical Monitor. Dosing with study drug should be suspended from 
the time steroid treatment is started. Complete blood count and lymphocyte subsets 
should be determined prior to starting steroid treatment and continue to be monitored 
weekly. Study drug may be resumed after discussion with the Medical Monitor when the 
following conditions are met: (1) treatment with steroids has been completed for at least
1 week; (2) absolute lymphocytes not <LLN; (revised per Amendments 07) (3) no 
lymphocyte subsets are below the discontinuation threshold (for Core Study only); (4) the 
investigator considers that the medical condition which required treatment with steroids 
has improved or resolved.  Weekly testing of lymphocyte subset counts (for Core Study 
only) and CBC with differentials is required for 4 weeks following resumption of study 
drug administration.  (revised per Amendment 04)

(revised per Amendment 06)
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for any 
efficacy analyses.  (revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed.  Subjects who are on anticoagulants may have a variable dose but should have 
stable anticoagulation control for at least 4 weeks before randomization. They may be 
required to stop their anticoagulant medication prior to CSF collection and then restart 
this medication after the LP procedure, as per local guidelines.  (revised per 
Amendment 04)

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.    (revised per Amendment 05)
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any 
other antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and
clopidogrel (or any other antiplatelet drug which is not aspirin) in combination are also 
Page 285 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 72 of 164
permitted but subjects who are on such a combination of antiplatelet drugs may be 
required to stop 1 or more of these antiplatelet drugs before the LP procedure and restart 
after the LP as per local guidelines.   

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, are permitted.   
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Page 286 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 73 of 164
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study 
drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator (or if regionally required, the head of the medical institution or the 
designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
Page 287 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 74 of 164
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6,
Table 7, and Table 14.  (revised per Amendment 07) A complete physical examination will 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, and skin, and a neurological examination (including the Brief Smell 
Identification Test [Sensonics Inc.]). 
(revised per Amendment 04).  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Significant findings at the Screening Visit will be recorded on the Medical History 
and Current Medical Conditions eCRF.  Changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization.
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
Page 288 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 75 of 164
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6, Table 7, and Table 14.  
(revised per Amendment 07) These assessments should be administered in the morning (or, if 
not possible, consistently at the same time of day) and should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  At the 
Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), 
CBB, ISLT (delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The 
CBB may be repeated multiple times if required for the subject to pass completion and 
integrity criteria.  At the Baseline Visit, the assessments are to be conducted in the following 
order: MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed 
recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
Alzheimer's Disease Assessment Scale - cognitive subscale:  Discussed in Section 9.2.3.  
(revised per Amendment 05)
Clinical Dementia Rating:  The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
ISLT:  The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects will read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Page 289 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 76 of 164
CogState Brief Battery:  The CBB is a computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.

Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.

One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
Functional Assessment Questionnaire: The caregiver or informant provides performance 
ratings (from 0 to 3) on 10 complex activities of daily living performed within the preceding 
4 weeks.  Scores range from 0 (independent) to 30 (dependent).  (revised per Amendment 04)
Page 290 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 77 of 164
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6, Table 7, and Table 14 according to standard 
quality control and normalization procedures for measurements of the whole brain and total 
ventricular volume.  (revised per Amendment 07) Measurements of the right and left 
hippocampal volumes will be based on a validated algorithm and conducted in the same 
laboratory.  Additional analysis of regions of interest and cortical thickness may also be 
performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of elenbecestat
(E2609).  For subjects who consent to CSF sample collection, CSF samples will be collected 
for the determination of elenbecestat (E2609) concentrations. (revised per Amendment 02)  
Analyses of metabolite concentrations may be performed, depending on emerging data from 
other studies with elenbecestat (E2609).
Page 291 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 78 of 164
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A 2nd PK blood sample will be collected as close as possible in time to the 
LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the 1st report of an SAE or severe unexpected AE 
and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal (Section 9.5.1.3.3).  The timing of the Baseline LP needs 
to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization 
timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  (revised per Amendment 04)  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 levels and activity.  (revised per 
Amendment 04)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but
did not provide a postrandomization sample will be approached to consider reconsenting to 
Page 292 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 79 of 164
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses.  Aβ(1-x) in both CSF and plasma will be measured using a modified 
commercially available enzyme-linked immunosorbent assay (ELISA).  The pre- and 
postscreening analysis of CSF Aβ(1-42), Aβ(1-40), t-tau, and p-tau will be performed using 
commercially available ELISAs.  (revised per Amendment 04)  BACE1 levels will be 
measured using internally developed fluorescence resonance energy transfer and ELISA 
based assay(s).  Substrates of BACE1 inhibition may also be explored using Western blots or 
other amenable methodology if clinical observations warrant and if analytes can be reliably 
tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
For subjects who consented to CSF sample collection, CSF samples from the Baseline Visit 
will also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, 
but not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, 
or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6, Table 7, and 
Table 14.  (revised per Amendment 07) 
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of elenbecestat (E2609). Details 
of which genotype/phenotype data will be applied to the analyses of efficacy, safety or PK 
will be discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
Page 293 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 80 of 164
development of AEs, or underlying AD.  Variations in elenbecestat (E2609) exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
single–nucleotide polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of Core Study treatment (or at the Core Study ED Visit if the 
subject has received study drug for at least 39 weeks).  (revised per Amendment 07) 
Longitudinal amyloid PET imaging will only be conducted on subjects with Screening PET 
scans performed for this study (ie, historical scans cannot be used for the longitudinal 
analyses) (Table 6).  (revised per Amendments 02 and 05)  PET scanning will be performed 
with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of elenbecestat (E2609).  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6, Table 7, and Table 14 will also be conducted. (revised per Amendment 
07)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during 
treatment, and posttreatment for exploratory immunomodulatory and immune-based 
analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal
relationship with the medicinal product.  For this study, the study drug is elenbecestat
(E2609).  
Page 294 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 81 of 164
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not necessary 
to report every sign or symptom as a separate AE if the overall disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, discontinuation of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit during the Core Study (Visit 20, as shown in 
Table 7, for subjects who do not enter the OLE Phase) or the last Visit during the OLE Phase 
(Visit 34 as shown in Table 14, for subjects who participate in the OLE Phase).  (revised per 
Amendment 07)  Subjects who fail screening primarily due to AE(s) must have the AE(s) 
leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
collected for 3 months after the last dose of study drug, (ie, through to the final Follow-Up 
visit [Visit 20 for subjects who do not enter the OLE Phase or Visit 34 for subjects who 
participate in the OLE Phase]).  (revised per Amendments 04, 05, and 07)
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADAS-cog14, MMSE, ISLT and CBB (see 
Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment Period, 
and if this cognitive decline is considered by the investigator to be excessive relative to the 
subject’s recent AD history, this finding should be reported as an AE.  
Page 295 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 82 of 164
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following AEs will require the collection of information sufficient to provide a detailed 
description of the event, treatment and outcome to the Medical Monitor for the study: any 
treatment-emergent significant laboratory abnormality; any seizures, herpes zoster infection, 
severe infection; any moderate to severe drug rash or any rash lasting more than 72 hours 
(regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the final Follow-Up visit (Visit 20 for subjects who do not 
enter the OLE Phase or Visit 34 for subjects who participate in the OLE Phase), or until 
resolution, whichever comes first.  (revised per Amendment 07) All SAEs must be followed 
to resolution or, if resolution is unlikely, to stabilization. (revised per Amendment 04)
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Page 296 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 83 of 164
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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)
Page 297 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 84 of 164
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.  
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6, Table 7, and Table 14 show 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 07)
See Section 9.3.3 and Appendix 6 for safety criteria for discontinuation from study 
drug-related to absolute counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset
counts.
Page 298 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 85 of 164
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening, Baseline, and Visit 21 only)  (revised per Amendment 02
and 07)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte T and B cell subset analyses (see Table 5).  Regulatory T cells (revised per 
Amendment 04)
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HbsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (including but not limited to CD3, CD4, CD8, CD45, CD19, 
CD16, CD56, and CD14) and absolute lymphocyte counts will be measured in order to 
provide the lymphocyte subset data as shown in Table 5.  In addition, Regulatory T cells will 
be measured.  Current sponsor data supports the literature showing there is an age-related 
decline in lymphocyte subsets (see Appendix 5). These data have been used to revise the 
LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts 
to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively) (revised per 
Amendments 02 and 04).  
Page 299 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 86 of 164
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
(Table 5 revised per Amendment 04)
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6, Table 7, and Table 14 by a validated method. (revised per 
Amendment 07) Measurements of sitting BP and heart rate will be obtained.  All BP 
measurements should be performed on the same arm, preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7 and Table 14.  (revised per Amendment 07) 
These examinations will include the cardiovascular system, respiratory system, and 
neurological system.  Health status will be evaluated by brief evaluation of the eyes, ears, 
nose, throat, and other physical conditions of note.  The subject must be queried regarding 
changes in physical status since the last examination.  A urogenital examination will only be 
required in the presence of clinical symptoms related to this region.  Documentation of the 
physical examination will be included in the source documentation at the site.  Only changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6, Table 7, and Table 14.  
(revised per Amendment 07) During the Core Study, twelve-lead standard ECGs will be 
Page 300 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 87 of 164
recorded in triplicate (1 minute apart) after subjects have been resting in the supine position 
for at least 5 minutes. During the OLE Phase, a single 12-lead ECG will be recorded after 
subjects have been resting in the supine position for at least 5 minutes.  If the QTcF is greater 
than 450 ms on the first single 12-lead ECG, 2 additional 12 lead ECGs will be performed 1 
minute apart and the mean of the 3 QTcF values will be calculated. (revised per Amendment 
07)
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6, Table 7, and 
Table 14. (revised per Amendment 07) Additional safety MRI scans can be performed at 
unscheduled visits if clinically necessary.  MRI acquisition and interpretation will be 
organized centrally to ensure reproducibility and consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2 Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, 18, 20, and 32.  (revised per Amendments
04 and 07) In the event of an Unscheduled Visit, the investigator in consultation with the 
sponsor will determine whether or not a safety MRI should be conducted.  If an ED Visit 
takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.
Page 301 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 88 of 164
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after study drug discontinuation; as well as 4 Follow-Up Visits at 2, 
4, 8 and 12 weeks after the last dose of Core Study treatment or 2 Follow-Up Visits at 4 and 
12 weeks after the last dose of OLE treatment.  (revised per Amendments 04 and 07) 
Subjects will also undertake an Unscheduled Visit (with MRI) at approximately 30 days after 
the visit at which such MRI features were first identified.  Additional visits may be arranged 
if clinically indicated in the opinion of the investigator, and may occur later than 12 weeks 
after the final dose of study drug.
9.5.1.5.8
DERMATOLOGIC ASSESSMENT
During the Core Study, centralized skin assessments, using standardized photography, will be 
performed by a reviewing dermatologist at the times shown in Table 6 and Table 7.  During 
the OLE Phase, all dermatologic assessments will be performed by the investigator at the 
times shown in Table 14.  (revised per Amendment 07) All assessments will specifically 
include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGIC EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6, Table 7, and Table 14.  (revised 
per Amendment 07) Details of these examinations will be captured in an eCRF.  The 
neurological examinations will monitor for new symptoms and signs which will then alert the 
investigator to consider new CNS pathology (especially slowly-evolving neurological 
conditions that may not lead to prominent symptoms).  Examples of neurological signs that 
may indicate new CNS pathology that may need further investigation include (but not limited 
to) visual disturbance, dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, 
paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or 
cognitive decline in excess of expectations based on the subject’s recent history.  In such a 
situation, the investigator should consider (but not limited to) demyelination in the 
differential diagnoses, and should discuss with the sponsor’s medical monitor further 
Page 302 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 89 of 164
investigations or treatment, which will be decided case by case.  Neurological examinations 
will also include the assessment of cranial nerve function, especially the olfactory nerve; the 
Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits to 
objectively test olfaction.  Treatment-emergent abnormal neurological findings should be 
reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening and Visit 21, females of childbearing potential will have a serum pregnancy 
test.  At Baseline and during the Treatment Period, urine samples will be obtained from 
females of childbearing potential for pregnancy tests (see Table 7 and Table 14). (revised per 
Amendment 07)
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6, Table 7 and Table 14.  (revised per Amendment 07) A “yes” 
answer to Type 4 or 5 suicidal ideation or a “yes” response to any suicidal behavior queries 
will trigger additional psychiatric evaluations by a psychiatrist to determine how the subject 
is to be managed clinically.  All sites are required to identify a psychiatrist for referral 
purposes.  The subject’s ability to continue to participate in the study will be determined by 
the investigator in consultation with the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
The Schedule of Procedures/Assessment is described in this section for the Core Study only.  
The Schedule of Procedures/Assessment for the OLE Phase is provided in Appendix 6, 
Table 14. (revised per Amendment 07)
Page 303 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 90 of 164
9.5.2.1
Schedule of Procedures/Assessments
Table 6
presents the Schedule of Procedures/Assessments for the Core Study 
Prerandomization Phase.  Screening assessments will be organized into 4 tiers (see below and
Figure 2). Table 7 presents the Schedule of Procedures/Assessments for the Core Study 
Randomization Phase.
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary)a
X
X
Demographics
X (Tier 1)
Medical historyb
X (Tier 1)
Prior/concomitant medicationsc
X (Tier 1)
X
Vital signs including weightd
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTe
X (Tier 1)
X
MMSEe
X (Tier 1)
X
CDRe
X (Tier 1)
X
FAQe
X (Tier 1)
X
ADAS-cog14
e
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGf
X (Tier 2)
X
Blood and urine for clinical laboratory testsg
X (Tier 2)
X
Blood for lymphocyte subset analysesh
X (Tier 2)
X
Blood for Ig analysesi
X (Tier 2)
X
Blood for viral screenj
X (Tier 2)
Blood for thyroid function testsk
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIl
X (Tier 3)
Amyloid PET scanm
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagea
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Page 304 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 91 of 164
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
(Table revised per Amendments 02 and 04)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of all 
Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
Subjects who initially consented to CSF collection and provided a baseline CSF sample but did not provide a 
postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample collection 
even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
For those subjects who do consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or 
at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to 
be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each individual subject. If the 
LP and cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used 
for PK and PD assessments.  A CSF sample will also be stored for testing in the event that the subject develops 
TEAEs that warrant further investigation (eg, treatment-emergent infection). (revised per Amendments 01, 02, and 
04) 
b:
To include:  mild cognitive impairment and AD history; history of TB, vaccination history against and infections due to 
varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include:  onset, duration, relapse frequency, severity, and 
Page 305 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 92 of 164
treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization can be 
extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory 
tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
c:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
d:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
e:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should 
be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At the 
Screening Visit, the recommended order of assessments is:  MMSE, ISLT (immediate recall), CBB, ISLT (delayed 
recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
f:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
g:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
h:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD19 (B cells), CD16/CD56 (natural killer cells) and CD14 (macrophages).  
Regulatory T cells will also be measured.  Viability staining may also be employed.  Whenever unscheduled 
lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a CBC with 
differentials, must also be repeated.   (revised per Amendments 02 and 04)
i:
Igs to be analyzed include IgG, IgA and IgM.
j:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
k:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine, and free thyroxine.
l:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.  MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
m:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an agent 
under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study.  The PET image will be centrally read for the purpose of determining eligibility 
for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the previous 12 
months and provided that the scan and result are considered acceptable by the central PET reading group.   (revised per 
Amendment 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops TEAEs that warrant further investigation 
(eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior 
exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurologic examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.  The Brief Smell 
Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of the neurological 
examination. (revised per Amendment 04)
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
Page 306 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 93 of 164
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
ED
b
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion 
criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological 
assessment via photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and 
urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (lymphocyte 
subset analyses)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (Igs)m
X
X
X
X
X
X
X
X
X
X
X
Blood samples (isolation of 
PBMCs)
X
X
X
Urine pregnancy test 
(females of CBP only)
X
n
X
X
X
X
X
X
X
X
X
Blood sample (storage for 
immune status)o
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 307 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 94 of 164
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
ED
b
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and 
exploratory biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and 
PDv
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 308 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 95 of 164
Footnotes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled, W2 = new Week 2 follow-up visit, W8 = new Week 8 follow-up visit.  (revised per Amendment 04)
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up 
Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (Visit W2, 19, W8, and Visit 20, respectively).  (revised per Amendments 04 and 05)  
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 4 posttreatment Follow-Up visits; 2, 4, 8, 
and 12 weeks after the last dose of study drug (Visits W2, 19, W8, and 20, respectively).  If clinically indicated, more frequent safety assessments can be made as UNS 
assessments or visits during the posttreatment Follow-Up period.  (revised per Amendment 04)
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at the previous Follow-Up visit.  (revised per Amendments 02 and 
04)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive 
decline in excess of expectations based on the subject’s recent history. The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves 
as part of the neurologic examination. (revised per Amendment 04)
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [NK cells] and CD14 [macrophages]) and absolute lymphocytes.  Regulatory T cells will also be measured. Viability staining may also be employed.  
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must 
also be performed along with assessment of AEs. (revised per Amendments 02 and 04)
Page 309 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 96 of 164
Footnotes for Table 7
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops a TEAE that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective 
agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors.  
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images 
in MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within 
the 7 days before Visits 14, 16, 18, and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety 
MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will 
be collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14, and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  Postrandomization CSF sample collection is scheduled at Visit 7 (or later postrandomization timepoint) and Visit 
18/ED.    If a postrandomization CSF sample is collected later than Visit 7, time-matched plasma PK samples are also required (see Footnote t).  All visits at which CSF 
samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. The timing of the Baseline LP 
needs to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and 
at a similar time of day (±1 hour) for each individual subject.  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  
A gravity drip collection method must be used.  If the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  The CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already 
Page 310 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 97 of 164
Footnotes for Table 7
stopped study drug, then no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. . Subjects who initially 
consented to CSF collection and provided a baseline CSF sample but did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendments 01, 02, and 04)  
w:
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 311 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 98 of 164
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the Core Study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.5.2, and Figure 2.  (Revised per amendment 07)
See Section 9.5 for a full description of the procedures and assessments to be performed 
during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the Core Study.  Additional samples may be taken at 
the discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety. (Revised per amendment 07)
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points × volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline Periods
Treatment and 
Follow-up
Periods
Blood
Chemistry
12
2 × 2 mL
10 × 2 mL
24 mL
Hematology
20
2 × 5 mL
18 × 5 mL
100 mL
Lymphocyte subset analysesa
20
2 × 4 mL
18 × 4 mL
80 mL
PBMC
4
1 × 16 mL
3 × 16 mL
64 mL
IgA, IgM, IgG
10
2 × 2 mL
8 × 2 mL
20 mL
PT, PTT for INR
2
2 × 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 × 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 × 4 mL
None
4 mL
Viral characterization
1
1 × 4 mL
None
4 mL
Vitamin B12
1
1 × 2 mL
None
2 mL
Serum pregnancy test
1
1 × 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 × 3 mL
None
3 mL
Sample for immune status
8
1 × 4 mL
7 × 4 mL
32 mL
PD sample
9
1 × 4 mL
8 × 4 mL
36 mL
PK analysis
7
1 × 3 mL
6 × 6 mL
39 mL
Pharmacogenetic sample
1
1 × 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
342 mL
422 mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 × 12 mL
2 × 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 312 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 99 of 164
a:
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, 
a CBC with differentials must also be performed. Therefore, for each unscheduled or repeat test, an additional 9 mL 
will be collected (5 mL for hematology and 4 mL for lymphocyte subset analyses) 
(Table 8 revised per Amendment 04)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with elenbecestat (E2609), in addition to mitigating 
clinical risk in the progression from 14 days of dosing in the MAD study to 18 months of 
treatment in this Phase 2 study.  Details are provided in Section 9.2.5.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the final follow-up visit (Visit 20 for subjects who do not enter 
the OLE Phase or Visit 34 for subjects who participate in the OLE Phase).  (revised per 
Amendments 04, 05, and 07)  However, any SAEs volunteered by subjects after this time 
point must be reported according to standard procedures.  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.
Page 313 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 100 of 164
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
Page 314 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 101 of 164
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
Page 315 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 102 of 164
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study 
drug in the Core Study (Visits W2, 19, W8, and Visit 20, respectively) or 4 and 12 weeks 
after the last dose of study drug in the OLE Phase (Visits 33 and 34) (see Section 9.1.2.3).
(revised per Amendments 04 and 07)
See Table 7 and Table 14 for full details of the 
assessments to be performed at these visits.  (revised per Amendments 05 and 07) Subjects 
who discontinue study drug early (as opposed to subjects whose dosing with study drug is 
temporarily suspended under Medical Monitor guidance) will not be permitted to restart 
study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal 
of consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary 
Page 316 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 103 of 164
reason, the subject may indicate 1 or more secondary reason(s) for withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Abuse or Diversion of Study Drug eCRF. (revised per 
Amendment 04)
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Page 317 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 104 of 164
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
9.7.1
Statistical and Analytical Plans
The statistical analyses of Core Study data are described in the following sections. Statistical 
analyses of OLE Phase data are provided in Appendix 6. (revised per Amendment 07) 
Analyses will be performed based on treatment group, which will be defined in the statistical 
analysis plan (SAP). Additional analyses related to dose re-assignment will be performed for 
subjects who will be switched from elenbecestat (E2609) 5 or 15 mg to elenbecestat (E2609) 
50 mg.  Further details will be provided in the SAP, which will be finalized before database 
lock. (revised per Amendment 06)
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

Safety and tolerability, which include incidence of TEAEs and SAEs, laboratory 
parameters, vital signs, and ECG parameters (revised per Amendment 05)
9.7.1.1.2
SECONDARY ENDPOINTS
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after from  4 weeks and 
up to 18 months of treatment 
Page 318 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 105 of 164

The population PK parameters of elenbecestat (E2609) in CSF and plasma, including the 
effect of intrinsic and extrinsic factors (including NAT2 phenotype)
(revised per 
Amendment 07)
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01, 02, 04, and 05)  
Change from baseline in:  

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) after at least 
4 weeks and at 18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment   

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and 
during posttreatment follow-up 

CSF amyloid and CSF BACE1 measurements after 4 weeks and 18 months of treatment
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months of treatment as measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain 
amyloid levels as measured

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose exploratory efficacy 
measurement.  (revised per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable elenbecestat
(E2609) plasma concentration accompanied by a documented dosing history. (revised 
per Amendment 07)

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
Page 319 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 106 of 164
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The number of randomized subjects enrolled at each site will be 
summarized by treatment group.  The primary reasons for screen failures (did not meet 
inclusion or met exclusion criteria, AE, lost to follow-up, withdrawal of consent, and other) 
will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized by treatment group using descriptive statistics.  Continuous demographic and 
baseline variables include age, MMSE and FAQ; categorical variables include sex, age group 
(≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014 or higher).  
(revised per Amendment 04) The number (percentage) of subjects who took prior and 
Page 320 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 107 of 164
concomitant medications will be summarized on the Safety Analysis Set by treatment group, 
Anatomical Therapeutic Chemical class, and WHO DD preferred term.  Prior medications 
will be defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the date of the last dose.  All medications will be 
presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05)
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
There is no primary efficacy endpoint.  (revised per Amendment 05)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 
18 months.  Data from early discontinuations will also be included. 
(revised per 
Amendment 05)
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01, 02, 04, and 05)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months.  Data from early discontinuations will also be 
included. (revised per Amendment 04)

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 
18 months of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 
months of treatment, and during posttreatment follow-up 

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and 
up to 18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by 
vMRI

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI 
Page 321 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 108 of 164

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid 
levels
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for elenbecestat (E2609) concentration listings and for 
summaries of elenbecestat (E2609) concentrations in plasma and CSF by dose and day.  
elenbecestat (E2609) metabolite PK data may also be listed and summarized. (revised per 
Amendment 04)
A population PK approach will be used to characterize the plasma PK of elenbecestat
(E2609).  For this approach, plasma PK data from this study will be pooled with relevant data 
from Phase 1 studies.  As appropriate, the effect of covariates on the PK of elenbecestat
(E2609) will be evaluated.  The PK model will be parameterized for oral clearance (CL/F) 
and apparent volume of distribution (Vz/F) for elenbecestat (E2609). Derived exposure 
parameters such as steady state area under the concentration time curve (AUC) and average 
concentration (Cavg) of elenbecestat (E2609) and other derived parameters will be calculated 
from the model using the individual estimates parameterized for oral clearance and dosing 
history.  (revised per Amendment 04)
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Page 322 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 109 of 164
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  The percentage change from baseline in CSF 
Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months of treatment will be analyzed and presented 
graphically. (revised per Amendment 05)  Baseline levels and changes in t-tau and p-tau will 
be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  (revised 
per Amendment 04)  
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
elenbecestat (E2609) dose, plasma, and CSF exposure will be initially explored graphically 
and any emergent relationship will be explored through population PK/PD modeling. The 
PK/PD relationship between plasma PK parameters with other biomarkers may also be 
explored using similar methods.  (revised per Amendment 04)  
The relationship between plasma and CSF exposure to elenbecestat (E2609) and the clinical 
efficacy scales (eg, MMSE, CDR) will be explored graphically.  Additionally, the 
relationship between plasma exposures of elenbecestat (E2609) and select lymphocyte 
parameters will be explored graphically, and any emergent relationship will be explored 
using population-based modeling methods.  (revised per Amendment 04)  
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, vital sign measurements, and cognitive decline assessment such as CBB will be 
summarized by treatment group using descriptive statistics.  (revised per Amendment 05)
Page 323 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 110 of 164
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The cumulative number and percent of subjects will be presented by 
treatment group.  Duration of exposure will be summarized using descriptive statistics as 
continuous variable as well as categorical variable in 3-month intervals and the number and 
percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).
Page 324 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 111 of 164
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Page 325 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 112 of 164
Lymphocyte subsets measured (including but not limited to CD4 [T helper cells], CD8 
[cytotoxic T cells], CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 
[macrophages] and regulatory T cells) will be summarized in the same manner as other 
laboratory parameters.  Mean lymphocyte subsets and the mean change from baseline in 
lymphocyte subsets will also be displayed graphically over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include CBB (Section 9.7.1.6).  (revised per Amendment 05)
Page 326 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 113 of 164
9.7.2
Determination of Sample Size
A total of 15 subjects per dose group is deemed sufficient to derive adequate safety and 
PK/PD data to aid in the selection of appropriate doses and the design of the Phase 3 studies 
that may be planned subsequently.  (revised per Amendment 05)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full elenbecestat
(E2609) clinical development program, the sponsor will unblind safety, PK, and PD data on 
an ongoing basis and perform interim analyses of these data.  Investigators, other clinical site 
staff, subjects, caregivers/informants, and study team will remain blinded to study treatment.  
(revised per Amendments 03 and 05)
An interim safety analysis will also be conducted when all subjects have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)  
9.7.4
Other Statistical/Analytical Issues
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 327 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 114 of 164
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Page 328 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 115 of 164
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology.
2007;68:1588-95.
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 329 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 116 of 164
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association 
workgroups 
on 
diagnostic 
guidelines 
for 
Alzheimer's 
disease.
Alzheimers Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 330 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 117 of 164
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 331 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 118 of 164
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 332 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 119 of 164
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 333 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 120 of 164
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 334 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 121 of 164
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 CTA 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 CTA 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 CTA 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.
Page 335 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 122 of 164
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.
Page 336 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 123 of 164
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5 g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Female:
>3.0 – 5.032
Female:
>5.0 – 20.032
Female:
>20.032
Page 337 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 124 of 164
Grade 1
Grade 2
Grade 3
Grade 4
Male:
>44 – 3.0 x 44
Male
>3.0 – 5.044
Male:
>5.0 – 20.044
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 338 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 125 of 164
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 339 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 126 of 164
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1 through Listing 5.  Medications permitted with 
restrictions are listed in Listing 6 through Listing 8.  (revised per Amendment 04) These may 
not be all-inclusive listings.  Please contact the medical monitor(s) if the investigators have 
any questions or concerns regarding any medication not listed that your subjects may be 
taking before enrollment or start during the course of the E2609-G000-202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 340 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 127 of 164
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Biaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 341 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 128 of 164
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 342 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 129 of 164
Listing 2 Prohibited Medications Within 5 Half-lives or 60 days, Whichever is Longer, 
Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa,b and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
b:
During the treatment period of the study, short term (not more than 14 days) use of steroids up to 
the equivalent of prednisolone 40 mg OD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started. Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly. Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) absolute lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold (for Core Study only); (4) the investigator considers that the medical condition 
which required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset 
counts (for Core Study only) and CBC with differentials is required for 4 weeks following resumption of 
study drug administration.  (revised per Amendment 04)
Page 343 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 130 of 164
Listing 3 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 344 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 131 of 164
Listing 4 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 345 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 132 of 164
Listing 5
Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last 
Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 346 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 133 of 164
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Final Follow-Up Visit 
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 347 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 134 of 164
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, 
Oramorph SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
Page 348 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 135 of 164
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
PRN = Pro re nata
Page 349 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 136 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 350 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 137 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Page 351 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 138 of 164
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 352 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 139 of 164
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 353 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 140 of 164
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 354 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 141 of 164
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 355 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 142 of 164
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Page 356 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 143 of 164
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Relaxed
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 357 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 144 of 164
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 358 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 145 of 164
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
Page 359 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 146 of 164
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or 
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and
Table 12), and a 10% cut value is applied to each of the 3 CD markers of interest the 
following age-adjusted LLN values are generated: 
Page 360 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 147 of 164
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 361 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 148 of 164
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 362 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 149 of 164
Appendix 6
Open-Label Extension Phase 
(revised per Amendment 07)
PRIMARY OBJECTIVE

To assess the long-term safety and tolerability of daily dosing with elenbecestat (E2609)
50 mg in mild cognitive impairment (MCI)/Prodromal subjects and in subjects with Mild 
to Moderate Dementia due to Alzheimer's Disease
SECONDARY OBJECTIVES

To explore the long-term effects of elenbecestat (E2609) on clinical status by assessment 
of: 
a.
The Mini-Mental State Examination (MMSE)
b. The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the long-term effects of elenbecestat (E2609) on:
a.
vMRI including total hippocampal volume, left and right hippocampal volume, 
whole brain volume, and total ventricular volume with up to 24 months of 
treatment in the OLE Phase.
b. Plasma amyloid at 12 and 24 months of treatment in the OLE Phase
ELIGIBILITY CRITERIA
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.
Inclusion:
1. Subjects who complete the 18-month treatment and the 12-week follow-up period 
(Visit 20) in the Core Study and whose Visit 20 falls within a 4-week window from the 
start of the Open-label Extension (OLE) Phase (Visit 21).  Permission must be obtained 
from the Medical Monitor if Visit 21 is to occur more than 4 weeks from Visit 20.
2. Subjects must continue to have an identified caregiver or informant who is willing and 
able to provide follow-up information on the subject throughout the course of the OLE 
Phase. 
Exclusion:
1. Subjects who discontinue study drug prematurely during the Core Study are not eligible 
to participate in the OLE Phase.
Page 363 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 150 of 164
2. Subjects with any active infection within 4 weeks of Visit 21. 
3. Subjects with absolute lymphocyte count below the Lower Limit of Normal (LLN) within 
10 days of Visit 21.
4. Subjects who develop the following conditions from the time of screening for the Core 
Study to the start of the OLE Phase: 
a.
Hepatic impairment, with total bilirubin greater than 1.5 × upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7.  Subjects with 
Gilbert’s syndrome need not be excluded on the basis of an elevated bilirubin, 
provided that they have no other signs or symptoms suggestive of hepatic 
impairment.
b. Any contraindications to MRI scanning, including cardiac pacemaker/ 
defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices other 
than those approved as safe for use in MRI scanners).  
c.
Severe visual or hearing impairment that would prevent the subject from 
performing psychometric tests accurately.
d. Immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
e.
Chronic viral hepatitis.
f.
Tuberculosis (TB).
g. Ophthalmic shingles.
h. Ocular herpes simplex virus (HSV) infection.
i.
Any chronic inflammatory disease that is not adequately controlled or that 
requires systemic or ocular immunosuppressive or immunomodulatory therapy.  
Subjects with:  

Seasonal or perennial allergic rhinitis, asthma or chronic obstructive 
pulmonary disease where the condition is considered to be stable and 
adequately controlled by inhaled steroids need not be excluded.  

Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy 
and not on systemic immunosuppressive therapy need not be excluded.  

Cutaneous manifestations of immunological disease that do not require 
systemic immunosuppressive therapy or systemic immunomodulatory 
therapy need not be excluded (topical steroid treatment is permitted).
j.
Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the 
skin, or localized prostate cancer that did not require systemic therapy; these do 
not exclude the subject from OLE).
5. Subjects with prolonged QTcF interval at Visit 20 or Visit 21. Subjects with a single 
12-lead ECG QTcF >450 msec should have 2 additional ECGs performed at least 1 min 
Page 364 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 151 of 164
apart and the mean QTcF from the triplicate ECGs should be calculated. Subjects with a 
mean QTcF value >450 msec are not eligible to enter the OLE Phase.
6. Subjects with significant pathological findings on brain MRI including but not limited to: 
an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of 
cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective 
lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular 
territory, severe small vessel, or white matter disease; space occupying lesions; or brain 
tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 
1 cm at their greatest diameter need not be exclusionary).
7. Subjects who have a “yes” answer to the Columbia Suicide Severity Rating Scale 
(C-SSRS) suicidal ideation questions 4 or 5 at Visit 20 or Visit 21 or any suicidal 
behavior during the study prior to the start of the OLE Phase.
8. Female subjects of child bearing potential who meet any of the follow criteria:
a.
Do not agree to use a highly effective method of contraception (eg, total 
abstinence, an intrauterine device, a double-barrier method [such as condom plus 
diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or 
have a vasectomized partner with confirmed azoospermia) throughout the entire 
study treatment period and for 28 days after study drug discontinuation.
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexually active during the study treatment period 
or for 28 days after study drug discontinuation.
c.
Who do not agree to use the same contraceptive during the study treatment period 
or for 28 days after study drug discontinuation.
9. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Visit 20 or Visit 
21.  
10. Subjects with medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that are not stably controlled, or which, in the opinion of the investigator(s), could affect 
the subject’s safety or interfere with the study assessments.
11. Any other clinically significant abnormal findings in vital signs, ECGs and laboratory 
tests that would, in the investigator’s opinion, would affect the subject’s safety or 
interfere with study assessments during the OLE Phase.
STUDY DESIGN AND PLAN
The OLE Phase allows eligible subjects to receive elenbecestat (E2609) 50 mg for up to 24
months (2 years). 
Page 365 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 152 of 164
Subjects who are enrolled in the Core Study will have the option to participate in the OLE 
Phase provided that they complete the Core Study (which include 18 months of double-blind 
treatment and 12 weeks of Follow-up Period) and satisfy the entry criteria for the OLE Phase.  
Subjects who discontinue from study drug during the Core Study are not eligible to 
participate in the OLE Phase.  
Eligible subjects who choose to participate in the OLE Phase may enter the OLE Phase 
immediately following the completion of Visit 20 (ie, Visit 21 procedures may be completed 
on the same day as Visit 20).  Subjects who are eligible to participate in the OLE Phase but 
who do not transition to the OLE Phase on the day of Visit 20 may enter the OLE Phase any 
time within 4 weeks of Visit 20.  The Medical Monitor must be contacted if Visit 21 is to 
occur more than 4 weeks after Visit 20.  For all subjects, assessments performed at V20 may 
serve as baseline values for the OLE Phase (ie, results of assessments conducted at Visit 21) 
with exceptions of laboratory assessments and vital signs, which must be repeated if Visit 21 
occurs more than 10 days from Visit 20.   
During the OLE Phase, subjects will receive open-label elenbecestat (E2609) 50 mg per day 
for up to 24 months.  Subjects with pending INR and serum pregnancy test results (females 
subjects of child bearing potential only) but who are otherwise qualified may begin OLE 
dosing at Visit 21; however, these subjects must discontinue study drug treatment 
immediately if either test result meet the exclusion criteria.
Safety assessments will be performed as described in Table 14.  Subjects may discontinue 
from study drug for any reason.  Subjects who complete 24 months of OLE treatment or who 
discontinue the study drug must comply with the Early Discontinuation Visit (within 7 days 
after the last dose of study drug) and the Follow-Up Visits (weeks 4 and 12 after the last dose 
of study drug). 
The study will end when the last visit for the last subject has completed the OLE Phase.
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason. Subjects who discontinue study drug 
prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study 
drug.  Subjects who discontinue from treatment during the OLE will have 2 posttreatment 
Follow-Up visits at 4 and 12 weeks after the last dose of study drug. 
Page 366 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 153 of 164
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug should be collected on the ED from study drug electronic 
case report form (eCRF) page (see Protocol Section 9.5.5). In addition, the date of last dose 
of study drug will be recorded on the Study Drug Dosing eCRF page. 
Safety-related criteria for discontinuation of study drug include the following:  
1. Absolute lymphocyte count will be monitored during the study. Should a subject develop 
lymphocytopenia (less than 800/mm3 or LLN, whichever is higher), a confirmation test 
should occur as soon as possible but no later than within 5 days with a repeat test of 
absolute lymphocytes. If confirmed, study drug administration should be interrupted for a 
minimum period of 2 weeks. Restart of study drug may take place only when absolute 
lymphocyte count returns to greater than LLN. Absolute lymphocyte count will be 
measured 4 weeks after restart of study drug. Subsequent measurements of absolute 
lymphocyte counts will follow the schedule of assessments and any results showing a 
Grade 2 or greater lymphocytopenia (less than 800/mm3) should be handled as above. If a 
2nd occurrence of Grade 2 or greater lymphocytopenia (less than 800/mm3), that is 
confirmed on repeat testing, occurs within 6 months, then the subject should be 
discontinued permanently from the study drug.
2. A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (with the exception of oral or genital herpes as 
described in the next paragraph), will be discontinued from study drug and a 
dermatologic consult will be requested regardless of whether the rash is considered 
drug-related or due to other causes. For cases where the investigator suspects a drug rash, 
regardless of severity, the subject will be discontinued from study drug, a dermatologic 
consult will be requested, and a skin biopsy will be performed to confirm the diagnosis. 
The skin rash will be treated as per standard care and will be followed up until resolution 
regardless of etiology or severity.
3. Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug. Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
4. Development of any of the following features on MRI: vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation.  They will also undertake an Unscheduled Visit (with MRI) at 
approximately 4 weeks after the visit at which such MRI features were first identified.   
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
Page 367 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 154 of 164
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
5. Pregnancy
6. A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs.
7. A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs.
Treatments
During the OLE Phase, all subjects will receive open-label elenbecestat (E2609) 50 mg once 
a day.  Each subject will take 1 tablet orally QD, with food. Please refer to Table 14 for 
specific information on drug administration on days when PD sampling is to be performed. 
EXTENSION PHASE ASSESSMENTS
Safety assessments will continue to be monitored according to the Schedule of Assessments 
and all adverse events (AEs) and serious adverse events (SAEs) recorded.  All safety 
assessments (eg, physical examinations, neurological examinations, vital signs, hematology, 
blood chemistry, serum and urine pregnancy test for females of child bearing potential, safety 
MRI and vMRI) will be performed as described in Table 14.  The number of blood samples 
and the total volume of blood that will be collected throughout OLE Phase is summarized in 
Table 13.  
There will be no centralized dermatological assessments in the OLE Phase; however, 
dermatological assessments will be performed by the investigator at every scheduled visit 
and as needed, at an unscheduled visit. These assessments will specifically include evaluation 
of any areas of depigmentation or drug-induced vitiligo as well as any evidence of rash. 
Subjects will also be questioned by the investigator at each visit to identify any changes that 
might represent a drug-induced rash/reaction or infection. Subjects and their study partners 
will be instructed to contact the investigator if they see any lesions or other symptoms that 
might be associated with a drug-induced rash/reaction or infection, so that such AEs can be 
reviewed promptly. 
Full neurologic examinations will be performed at the start of the OLE (Visit 20 or 21), and  
every 6 months during the OLE treatment period.  An additional neurologic examination will 
also be performed at the final Follow-Up Visit. The neurologic examinations will include 
Page 368 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 155 of 164
muscle strength testing and assessment of cranial nerves including olfaction, with the use of 
the Brief Smell Identification Test, as well as other parts of the central nervous system 
(CNS).
Complete blood counts and percentages will be measured (by a centralized laboratory) every 
scheduled visit.  Additional blood sample will be collected and stored at each scheduled visit; 
these samples may be used for exploratory biomarker analyses or be analyzed  in the event 
that the subject develops treatment-emergent adverse events that warrant further 
investigation.
Peripheral blood mononuclear cells (PBMCs) will be collected every scheduled visit and 
posttreatment for exploratory immunomodulatory and immune-based analyses.  These blood 
samples will be collected at every visit and stored in the event that the subject develops 
treatment-emergent adverse events that warrant further investigation (eg, treatment-emergent 
infection), these samples may be tested to determine whether the subject already had prior 
exposure to any suspected infective agents.
Safety brain MRI and vMRI assessments will be performed at the end of the OLE treatment 
period (Visit 32 or ED). Additional safety MRI scans are to be performed as clinically 
necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
beginning and at the end of treatment and a more general clinical assessment by the 
investigator, involving both the subject and the study partner, at all other visits.  
Blood sample for PD analyses will be collected at Week 53 (Visit 28), at the end of the OLE 
treatment period (Visit 32 or ED), and during the Follow-up Period (Visits 33 and 34). The 
plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory biomarker 
analyses.  The blood sample for PD analyses should be collected at fasting or at least 2 hours 
after the most recent meal.
Clinical assessments (MMSE and FAQ) will be administered every 3 months as described in 
Table 14.
The Follow-Up Visit will take place at weeks 4 and 12 after the last dose of study drug as 
described in Table 14.  These assessments will also be performed if a subject prematurely 
discontinues from the OLE Phase.
Page 369 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 156 of 164
Table 13
Summary of Blood Sample Volumes
Assessment
Total number of 
collection time pointsa
Number of time points x 
volume per collection (mL)
Total volume (mL)
OLE Treatment and Follow-
up Periods
Blood
Clinical Chemistry
14
14 x 2 mL
28 mL
Hematology
14
14 x 5 mL
70 mL
Lymphocyte subset 
analysesb
14
14 x 4 mL
56  mL
PBMC
14
14 x 16 mL
224 mL
PT, PTT for INR
1
1 x 3 mL
3 mL
Serum Pregancy Test
1
1 x 2 mL
2 mL
Sample for immune 
statusc
8
8 x 4 mL
32 mL
PD sample
5
5 x 4 mL
20 mL
Total volume whole blood collected
435 mL
OLE = Open-label Extension, PBMC = peripheral blood mononuclear cell, PT = prothrombin time,  PTT = partial 
thromboplastin time, INR = International Normalized Ratio, PD = pharmacodynamics.
a:
Total collection time points include a baseline sample at Visit 21 if not done at Visit 20; a baseline sample will be 
collected only if Visit 21 is conducted more than 10 days after Visit 20.
b:
Blood samples for lymphocyte subset analyses will be collected and analyzed at every visit; reports of the analyses will 
be sent to the Sponsor only.  
c:
Blood samples for will be collected and stored.   These samples may be used for exploratory biomarker analyses, or in 
the event that the subject develops treatment-emergent adverse events that warrant further investigation (eg, treatment-
emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any 
suspected infective agents.
STUDY DRUG SUPPLIES 
Elenbecestat (E2609) tablets of 50-mg dose strengths will be supplied.  Each subject will 
take 1 tablet per day.
SCHEDULE OF PROCEDURES/ASSESSMENTS
Table 14 presents the Schedule of Procedures/Assessments for the OLE Phase. 
Page 370 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 157 of 164
Table 14 Schedule of Procedures/Assessments in Study 202:  Open-label Extension Phase
Phase
Open-label Extension Phase
Period
Treatment
Follow-Upd
UNS 
Visite
Visita
21b
22
23
24
25
26
27
28
29
30
31
32
EDc
33
34
Day in OLE
1
15
29
57
85
183
274
365
456
547
638
729
757
813
Week in OLE
1
3
5
9
13
27
40
53
66
79
92
105
109
117
Weeks elapsed since 1st dose in OLE
0
2
4
8
12
26
39
52
65
78
91
104
108
116
Nominal months elapsed since first dose in OLE
0
1
2
3
6
9
12
15
18
21
24
25
27
Procedures/ Assessments
Routine physical examination with dermatologic 
review
Xf,g
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Inclusion and Exclusion criteria
X
Vital signs, including respiratory ratei
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Weight
Xf
X
X
X
X
Neurological examinationk
Xf
X
X
X
X
X
X
X
Concomitant medicationsl
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGn
Xf
X
X
X
X
X
X
X
Xh
X
Clinical biochemistry and urinalysis
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for PT and PTT for INR
X
Blood samples for lymphocyte subset analysiso
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for PD and exploratory biomarkersp
Xf
X
X
X
X
X
X
Blood samples (isolation of PBMCs)
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test (females of CBP only)q
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test (females of childbearing 
potential only)
X
X
Blood sample (storage for immune status)r
Xf
X
X
X
X
X
X
X
X
X
MMSEs
Xf
X
X
X
X
X
X
X
X
X
X
X
X
FAQs
Xf
X
X
X
X
X
X
X
X
X
X
X
X
Page 371 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 158 of 164
Phase
Open-label Extension Phase
Period
Treatment
Follow-Upd
UNS 
Visite
Visita
21b
22
23
24
25
26
27
28
29
30
31
32
EDc
33
34
Day in OLE
1
15
29
57
85
183
274
365
456
547
638
729
757
813
Week in OLE
1
3
5
9
13
27
40
53
66
79
92
105
109
117
Weeks elapsed since 1st dose in OLE
0
2
4
8
12
26
39
52
65
78
91
104
108
116
Nominal months elapsed since first dose in OLE
0
1
2
3
6
9
12
15
18
21
24
25
27
Procedures/ Assessments
C-SSRS
Xf
X
X
Clinical assessment of suicidal thinking and behaviort
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety MRI and vMRIu
Xf
X
X
X
Adverse events
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
Xv
X
X
X
X
X
X
X
X
X
Notes for Table 14
C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, OLE = Open-label Extension, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, UNS = unscheduled, vMRI = volumetric magnetic resonance imaging.
Page 372 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 159 of 164
a:
A window of ±3 days will be permitted for Visits 22 and 23.  A window of ±7 days will be permitted for Visits 24 and 25.  A window of ±10 days will be permitted for Visit 
26 to 32 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If a permitted visit windows is used, every effort should be made to bring the subject 
back in line with the “weeks elapsed since 1st dose in OLE” at subsequent visits.
b:
Visit 21 may occur on the same day or within 4 weeks of Visit 20 date. The Medical Monitor must be contacted if Visit 21 is to occur more than 4 weeks after Visit 20.  
Informed consent must be obtained prior to performing Visit 21 assessments.
c:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visits 33 and 34 respectively).
d:
All subjects, regardless of whether they complete all 24 months of treatment or discontinue study drug prematurely, will complete the 2 posttreatment Follow-Up Visits; (ie, 
Visits 33 and 34).  If clinically indicated, more frequent safety assessments can be made as UNS assessments or visits during the posttreatment Follow-up Period.
e:
Unscheduled visits may be conducted at any time that additional assessments, including MRI scans, are clinically indicated in the judgment of the investigator.  Note that not 
all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
f:
Result from Visit 20 will also serve as Visit 21 result. If the specified assessment was not performed at V20, it must be performed at Visit 21.
g:
Dermatologic assessment by the investigator must be performed at Visit 21 in addition to the centralized skin assessment (using standardized photography) performed at Visit 
20.
h:
Only if clinically significant abnormalities are found at Visit 33 and the investigator considers it necessary to repeat at Visit 34.
i:
Measurements of body temperature and sitting blood pressure and sitting heart rate will be obtained.
j:
Result from Visit 20 will also serve as Visit 21 result if Visit 21 occurs within 10 days from Visit 20. If Visit 21 occurs more than 10 days after Visit 20, the assessment must 
be repeated at Visit 21.
k:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part 
of the neurologic examination.
l:
Please refer to Section 9.4.7 which describes prohibited and permitted medications in the study.
m:
Result from Visit 20 will also serve as Visit 21 result if Visit 21 occurs on the same day as Visit 20. If Visit 21 occurs more than 1 days after Visit 20, the assessment must be 
repeated at Visit 21.
n:
Single 12-lead standard ECGs will be recorded.  If the QTcF is greater than 450 ms, perform 2 more 12-lead standard ECGs 1 minute apart and take the mean of the 3 QTcF 
values. 
o:
Reports of the lymphocyte subset analyses will be sent to the Sponsor only.  Lymphocyte subsets will include but are not limited to the following cell surface marker 
assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and absolute lymphocytes.  Regulatory T cells 
will also be measured. Viability staining may also be employed.
p:
PD blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at the same time of day.  All 
PD blood samples should be collected predose.
q:
If dipstick urinalysis performed at site is abnormal, a urine sample will be sent to the central laboratory for full urinalysis. 
Page 373 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 160 of 164
r:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
s:
The subject components of these assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  Ideally, the subject component 
of these assessments should be completed before more invasive assessments or procedures (eg, physical examination, ECG, blood draws).  
t:
The clinical assessment of suicidality will require input from both the subject and the study partner
u:
MRI imaging will be conducted on separate days from the scheduled visits.  Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long 
tau inversion recovery, and diffusion-weighted imaging sequence images in MRI will be read by an approved central reader.  MRI imaging should be conducted within 7 days 
before Visits 21 (where applicable) and 32.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  
v:
The subject will take the first dose of study drug at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined by the PI 
or Safety Physician for postdose medical observation.   Subjects with pending INR and serum pregnancy results may begin dosing at Visit 21 if they satisfy all other OLE 
entry criteria.
Page 374 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 161 of 164
EXTENSION PHASE STATISTICAL METHODS
Primary Endpoint

Safety endpoints: AE, vital sign, ECG, physical examination, clinical laboratory test, 
any relevant test of cognitive function to evaluate decline, and MRI parameter 
(microhemorrhage, vasogenic edema, and other clinically significant abnormalities).
Secondary Endpoint
Changes from Core Study and OLE baselines in 

MMSE and FAQ at each visit assessed in the OLE Phase

Plasma amyloid measurements at 12 and 24 months of OLE treatment

Total hippocampal volume, left and right hippocampal volume, whole brain volume, 
and total ventricular volume with up to 24 months of OLE treatment as measured by 
vMRI
OLE PHASE ANALYSIS SETS

The OLE Safety Analysis Set (OLE-SAS) is the group of subjects who receive at 
least 1 dose of study drug during the OLE Phase. 

The OLE Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 
1 dose of study drug during the OLE Phase and have at least 1 postdose efficacy 
assessment during the OLE Phase.

The OLE PD Analysis Set is the group of subjects who have at least 1 posttreatment 
PD measurement in the OLE Phase.
Safety Analyses
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be 
based on OLE Safety Analysis Set.  The incidence of AEs (including changes from baseline 
in physical and neurological examinations, and dermatological assessments), out-of-normal-
range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and changes from baseline in laboratory safety test variables, ECGs, 
safety MRI, vital sign measurements, and cognitive decline assessment such as MMSE will 
be summarized by using descriptive statistics.  
Efficacy Analyses
The following secondary efficacy endpoints will be summarized by descriptive statistics 
and/or graphs, using OLE-FAS:
Page 375 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 162 of 164

Changes from Core Study and OLE baselines in MMSE and FAQ scores

Changes from Core Study and OLE baselines in total hippocampal volume, left and 
right hippocampal volume, whole brain volume, and total ventricular volume at up to
24  months as measured by vMRI 
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis.
Pharmacodynamic Analyses
The OLE PD Analysis Set will be used for the summaries and analyses of PD biomarkers. 
The percentage change in plasma amyloid measurements from Core Study and OLE 
baselines to 12 and 24 months of OLE treatment will be analyzed and presented graphically.
SAMPLE SIZE RATIONALE
Subjects who complete the Core Study will have the option to participate in the OLE Phase.  
There is no sample size calculation for the OLE Phase.  
Page 376 of 1658


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 163 of 164
PROTOCOL SIGNATURE PAGE
(revised per Amendment 05)
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Investigational Product
Name:
Elenbecestat* (E2609)
* pINN (revised per Amendment 07)
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neurology Business Group
Eisai Inc.
Date
 Neurology Business Group
Eisai Ltd. 
Date
Neurology Business Group Eisai Inc.
Date
Page 377 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 07)
E2609-G000-202
Eisai
FINAL (V9.0):  01 Feb 2017
Confidential
Page 164 of 164
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and 
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment 
due 
to 
Alzheimer’s 
Disease 
(Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigational Product 
Name:
Elenbecestat* (E2609)
* pINN (revised per Amendment 07)
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 378 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page i of xx
REVISION HISTORY
Revisions to Version 7.0
New version/date:  Version 8.0 / 02 Nov 2016 (per Amendment 06)
Change
Rationale
Affected Protocol Sections
Subjects currently receiving
5 or 15 mg E2609 will be 
re-assigned to 50 mg E2609 
for the remainder of the 
double-blind treatment
period provided they will 
receive at least 12 weeks of 
double-blind treatment after 
the re-assignment, (ie, no 
dose reassignments past 
Visit 17).
As E2609 50 mg has been selected 
as the appropriate dose for Phase 3 
development, subjects should not
continue with doses that are not 
being advanced clinically.
Additionally, the re-assignment of 
subjects in E2609 5 and 15 mg to 
E2609 50 mg will further the 
safety and tolerability data in
subjects exposed to E2609 50 mg.
Synopsis 
Study Design
Number of Subjects
Sample Size Rationale
Section 7.1
Section 9.1
Section 9.1.2.1
Section 9.4.1
Section 9.4.4
Section 9.5.2
Clarified that one of the 
exploratory endpoints will 
analyze  change from 
baseline in CSF amyloid 
and CSF BACE1 
measurements from 
4 weeks and up to 
18 months of treatment  
only.  There will no 
analysis for treatment 
follow-up.
Correction
Synopsis 
Analysis for Exploratory 
Endpoints
Exploratory Objective
Section 8.3
Section 9.7.1.1.3
Section 9.7.1.6.3
The frequency of DSMB 
safety reviews after the
12 week interim safety 
analysis will be reassessed 
and details will provided in 
the DSMB charter.
The DSMB charter will provide 
full details of interim safety 
reviews.
Synopsis 

Study Design
Section 9.1
Removed the statement that 
subjects must be stable on 
AChEI or mementine to be 
included in the primary 
analyses.
This statement is no longer 
relevant as of Amendment 05.
Synopsis 
Concomitant 
Drug/Therapy
Section 9.4.7
Added a statement to 
specify that additional 
analyses will be performed 
for subjects with dose re-
assignment and details of 
these analyses and 
To clarify that the SAP will be 
finalized prior to database lock and 
it will provide full details of the 
analyses to be performed for this 
study. 
Section 9.7.1
Page 379 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page ii of xx
Revisions to Version 7.0
New version/date:  Version 8.0 / 02 Nov 2016 (per Amendment 06)
Change
Rationale
Affected Protocol Sections
treatment group definitions
will be provided in the 
statistical analysis plan
(SAP); clarified that the  
SAP will be finalized before 
database lock.
Grammatical, 
typographical, and 
formatting changes 
Throughout
Page 380 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page iii of xx
Revisions to Version 6.0
New version/date:  Version 7.0 / 26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Removed Stage B from protocol. In 
line with this decision, the study 
objectives and endpoints have been 
modified and subjects who 
discontinue study drug early for any 
reason will no longer be required to 
complete efficacy visits after last 
dose of study drug.
This study will no longer 
be a Proof-of-Concept 
study.  
Synopsis 
Study Protocol Title
Investigators
Sites
Study Period and Phase 
of Development
Objectives
Study Design
Early Discontinuation
Number of Subjects
Study Treatments
Efficacy Assessments
Safety Assessments
Statistical Methods
Study Endpoints
Analysis Sets
Efficacy and Biomarker 
Analyses
Analysis for the 
Primary/Secondary/Explo
ratory Endpoints
Pharmacokinetic 
Analyses
Pharmacokinetic 
/Pharmacodynamic 
Analyses
Interim Analyses
Sample Size Rationale
Section 6
Section 7
Section 8
Section 8.3
Section 9.1
Section 9.2.1
Section 9.2.3
Section 9.2.4.4
Section 9.2.5
Section 9.3
Section 9.4.3
Page 381 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page iv of xx
Revisions to Version 6.0
New version/date:  Version 7.0 / 26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Section 9.4.4
Section 9.4.7
Section 9.2.5
Section 9.5.1.3.1
Section 9.5.1.4.2
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.4.1
Section 9.5.5
Section 9.7
Section 10
Updated Eisai contact information 
Change in personnel and 
move to Building 100
Title Page
Protocol Signature Page
Page 382 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page v of xx
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of investigational 
sites (from 40 to 35)
Feasibility

Synopsis -
o Study Design
o Sites
Section 6
Section 9.1
Section 9.3
Removed Exclusion Criterion No. 
44 for male subjects regarding 
restrictions on child bearing  
No longer a safety concern;
E2609 has not shown a 
deleterious effect on sperm in 
preclinical reproductive toxicity 
studies.

Synopsis:
o Exclusion Criteria
Section 9.3.2
Added option for subjects who 
provided a CSF sample prior to 
randomization but who declined the 
CSF sample collection after 4 weeks 
of dosing to provide a postdose CSF 
sample at any point in the study (ie, 
even after 4 weeks of dosing).
Reflects the added value of CSF 
data for the PK/PD secondary 
objective of this study.  In 
addition, given that PK steady 
state is achieved within the 1st 
2 weeks of initiation of dosing, 
data collected post Week 4 visit 
is still considered to be 
applicable in assessment of the 
steady state effect.

Synopsis -
o Pharmacodynamic
Assessments
Section 5.3
Section 9.1
Section 9.1.1.2
Section 9.5.1.3.3
Section 9.5.1.4
Table 6
Table 7
Table 8
Revised details of restrictions to 
anticoagulant therapy and short-
term steroid use revised/moved 
details regarding antiplatelet drugs 
to the main body of the protocol
To assist in subject recruitment 
and retention and considering 
that the strict restrictions were 
not necessary for subject safety

Synopsis -
o Concomitant 
Drug/Therapy
Section 9.4.7
Appendix 2
Removed the 33% decrease from 
baseline for CD4, CD8, and CD19 
as a trigger for more frequent 
testing of flow cytometry and 
CBCs. Additional safety 
monitoring for CD4, CD8, CD19, 
and CBCs will only be based on the 
population adjusted LLNs for 
clinically asymptomatic subjects. 
Experience to date has indicated 
significant variability within the 
normal range, both for increases 
and decreases. Absolute counts 
of lymphocyte subsets are more 
meaningful than percentage 
decreases for triggering more 
frequent monitoring.
Section 9.3.3
Table 1
Table 2
Page 383 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page vi of xx
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Added option to temporarily 
suspend study drug for subjects who 
are clinically asymptomatic but who 
meet CD4, CD8, or CD19 
discontinuation thresholds on 
2 consecutive tests.  Introduce rules 
for ability to re-start study drug (ie, 
rechallenge) in these subjects.   
Only 1 cycle of temporary 
suspension and rechallenge with 
study drug permitted for any 
individual subject.  
To assist in subject retention and 
to gain knowledge on the 
behavior of lymphocyte subsets 
on rechallenge.
Section 9.3.3
Table 1
Table 2
Added extra blood draw times with 
focus on lymphocyte subsets, 
CBCs, and immunoglobulins during 
the 12-week safety follow-up for all 
subjects.
To increase frequency of key 
safety monitoring parameters in 
post-treatment follow-up period 
so as to assess immunological 
changes after completion of 
study drug

Synopsis
o Study Design
o Safety Assessments
Section 9.1.2.2
Section 9.1.2.3
Section 9.2.5
Section 9.3.3
Table 7
Table 8
Section 9.5.1.5.7
Section 9.5.5
Clarified that the Functional 
Assessment Questionnaire is to be 
administered to the 
informant/caregiver, and not the 
subject.
Clarification

Synopsis
o Efficacy 
Assessments
Section 9.5.1.3.1
Added clarification that the Brief 
Smell Identification Test will be 
administered as part of the 
neurological examination
Clarification

Synopsis
o Safety Assessments
o Interim Analyses
Section 9.1.1.2
Section 9.5.1.2.1
Section 9.5.1.5.9
Table 6
Table 7
Page 384 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page vii of xx
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of randomized 
subjects in Stage A to n=60±20%
To allow for additional 
randomization based upon 
current number of subjects in 
screening at the time of 
amendment implementation

Synopsis
o Study Design
o No. of Subjects
Section 7
Section 9.1
Section 9.2.1
Section 9.2.5
Section 9.3
Section 9.7.3
Grammatical, typographical, and 
formatting corrections
Consistency
various
Page 385 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page viii of xx
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder of 
the study and the full 
E2609 clinical 
development program

Synopsis –
o Exploratory Endpoint 
Analysis
o Interim Analysis
Section 9.1
Section 9.1.1.2
Section 9.4.6
Section 9.7.1.7.1
Page 386 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page ix of xx
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.5
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Appendix 2, Listing 2
Page 387 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page x of xx
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
o
Inclusion/Exclusion
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.4.3

Section 9.3.1

Section 9.5.2

Table 6

Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/Exclusion

Section 9.3.2

Section 9.5.2

Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
Added to provide clarity 

Synopsis –
Page 388 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xi of xx
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
for the sites.
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1

Figure 2

Section 9.5.1.3.1

Section 9.5.2

Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3

Table 1

Section 9.5.2

Table 6

Table 7
Page 389 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xii of xx
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1

Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2

Table 6
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2

Table 6

Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3

Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2

Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2

Table 6

Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 390 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xiii of xx
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1

Section 9.1.1

Figure 1

Section 9.2.1

Section 9.2.2

Section 9.2.3

Section 9.2.4.3

Section 9.2.4.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.4.3

Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2

Section 9.7.1.1.3

Section 9.7.1.4

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.3

Section 9.7.4
Page 391 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xiv of xx
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 

Section 5.3
Page 392 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xv of xx
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
capacity to consent themselves.
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis –
o
Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 393 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xvi of xx
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis –
o
Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis –
o
Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis –
o
Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
o
Inclusion/Exclusion  
Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and  
International Normalized Ratio 
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
o
Inclusion/Exclusion 
Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
Page 394 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xvii of xx
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –
o
Study Design  

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol.  The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20 
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis –
o
Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis –
o
Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis –
o
Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline, 
during treatment, and post-
treatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF 
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis –
o
Assessments

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6
Page 395 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xviii of xx
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis –
o
Concomitant 
Drug/Therapy

Section 7.1

Section 9.4.7

Appendix 2, Listing 6
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis –
o
Analysis of Primary 
Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis –
o
Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Page 396 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xix of xx
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5.1

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis –
o
Study Endpoints

Section 9.7.1.2
Page 397 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page xx of xx
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.5

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 398 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 1 of 144
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-
Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects 
With Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
V6.0
29 Jun 2016 (Amendment 04)
V7.0
26 Sep 2016 (Amendment 05)
V8.0
02 Nov 2016 (Amendment 06)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 399 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 2 of 144
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-Finding Study To Evaluate 
the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigators
Investigators in the United States only (revised per Amendment 05)
Sites
Approximately 35 sites, United States only (revised per Amendments 01, 02, 04, and 05)
Study Period and Phase of Development
Approximately 32 months (revised per Amendment 05)
Phase 2
Objectives
Primary Objective (revised per Amendment 05)

To assess the safety (including immunological and hematological parameters) and tolerability 
of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with Mild to Moderate 
Dementia due to Alzheimer's Disease (referred to as mild to moderate AD throughout the 
protocol) (revised per Amendment 01)
Secondary Objectives (revised per Amendments 02 and 05)

To characterize the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of E2609 

To assess the effects of E2609 on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and up to
18 months of treatment 
Exploratory Objectives
(revised per Amendments 01, 02, 04, and 05)

To explore the effects of E2609 on CSF Aβ(1-40) and beta (β)-amyloid converting enzyme 1 
(BACE1) measurements from 4 weeks and up to 18 months of treatment 

To explore the effects of E2609 compared with placebo on various biomarkers.  Biomarkers 
to be explored may include but are not limited to: 
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
Page 400 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 3 of 144
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, by assessment of:  
a.
The 
Alzheimer’s 
Disease 
Assessment 
Scale 
–
cognitive 
subscale 
(ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of E2609 on measured clinical 
efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF amyloid isoforms, 
brain amyloid, and vMRI 

To explore relationships between both E2609 dose and exposure, with pharmacodynamic 
(PD) and safety endpoints 
Study Design
This will be a multicenter, placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common set of inclusion 
criteria, consistent with the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical 
research criteria for Mild Cognitive Impairment (MCI) due to Alzheimer’s Disease (AD) or mild to 
moderate AD, will be required for all subjects.  In addition, the MCI due to AD population will also 
be consistent with the research criterion for “Prodromal AD” in that episodic memory will be 
impaired on a list learning task (ISLT).  As the non-demented subjects will be consistent with the 
criteria for both MCI due to AD and Prodromal AD they will be identified as MCI/Prodromal 
subjects in this protocol.  The diagnosis of MCI/Prodromal AD or mild to moderate AD will be based 
on both clinical and biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists of 2 phases:  Prerandomization and Randomization.  The Prerandomization Phase 
(up to 60 days, plus an additional window of up to 30 days if required [revised per Amendment 02]) 
includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All screening assessments (within 
4 distinct tiers) must be completed, and eligibility to continue in the study confirmed, before any 
baseline assessments commence.  Following successful completion of the Prerandomization Phase, 
eligible subjects will be randomized and will enter the Randomization Phase, which will consist of 
2 periods:  Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
The study will be limited to approximately 35 sites in the United States.  (revised per Amendments 
01, 02, and 04)  Subjects will initially be randomized 1:1:1:1 to 4 treatment groups (5, 15, or 50 mg 
Page 401 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 4 of 144
E2609 or placebo) within each of the 2 clinical populations.  (revised per Amendments 01, 04, 05, 
and 06) In addition to the placebo group, 3 E2609 doses will be used to reduce CSF amyloid β levels 
by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at steady 
state.  PK/pharmacodynamic (PD) modeling has shown that these doses should achieve these targets 
when administered once daily (QD) with food, and these doses will be evaluated based on the 4-week 
(or later) assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement.  (revised per Amendment 02)  Upon implementation of Amendment 06, at the next 
regularly scheduled visit, subjects receiving E2609 5 or 15 mg who have not yet completed Visit 17 
(Week 66), will be re-assigned in a blinded manner to E2609 50 mg for the remainder of the 
double-blind treatment period.  In order to maintain the blind, all subjects who have not yet had 
Visit 17 will go through the same procedures with the placebo-randomized subjects continuing to 
receive placebo and those randomized to E2609 50 mg continuing to receive 50 mg. (revised per 
Amendment 06)
Safety data will be monitored in a blinded fashion on a regular basis.  In addition, approximately 
every 3 months from the time the 1st subject is randomized into the study through the time the last 
subject is randomized, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  (revised per Amendment 06) 
The DSMB will make recommendations to Eisai after each review as to whether any change(s) to the 
study are necessary.  (revised per Amendments 01, 04, and 05)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD profiles will 
be performed on baseline data and samples collected after at least 4 weeks of treatment.  (revised per 
Amendment 05)  These interim analyses, as well as analyses of safety data, will be performed on an 
ongoing basis throughout the study.  Refer to the Interim Analysis section for more detail. These data 
will be used to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions 
from baseline in CSF Aβ(1-x) levels.  (revised per Amendments 01 and 02)  The median and mean 
percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks or more of treatment for 
each dose of E2609 and the 90% confidence interval (CI) for the median will be derived.  In addition, 
exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the observed PK and 
PD data and will relate the average steady state plasma concentration of E2609 to CSF Aβ(1-x) 
percentage reduction from baseline determined after at least 4 weeks of dosing.  (revised per 
Amendments 01, 02, 03, 04 and 05)  
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug early) an 
interim safety analysis will be conducted by Eisai and the DSMB. At the completion of this interim 
safety review, the frequency of subsequent unblinded safety reviews will be re-evaluated by the 
DSMB and the Sponsor and this information will be provided in the DSMB charter. (revised per 
Amendment 06) Subjects will continue study drug while the DSMB reviews all the available safety 
data.  (revised per Amendments 01, 04, and 05). (revised per Amendment 06)
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also 
be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug. (revised per Amendments 04 and 
05)  
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study 
drug prematurely, will complete 4 post-treatment Follow-Up Visits: 2, 4, 8, and 12 weeks after the 
last dose of study drug.  If clinically indicated, more frequent safety assessments can be conducted as 
Page 402 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 5 of 144
part of unscheduled visits during the post-treatment Follow-Up Period. (revised per Amendment 04)
Number of Subjects
Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be screened to provide 
approximately 60 (±20%) randomized subjects (a target of approximately 15 subjects per treatment 
arm).  There will be no limit to the number of subjects randomized from either clinical cohort.  
(revised per Amendments 01, 02, 04, and 05)
Inclusion Criteria
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01) 
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 standard deviation (SD) from age adjusted norms in 
delayed recall on the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from 
age-adjusted norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT 
immediate recall, or 1 of the learning and memory components of the CBB).  (revised per 
Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
Page 403 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 6 of 144
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Exclusion Criteria (revised per Amendment 04)
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and <1 cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures  (revised per Amendments 01 
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for the 
testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal malformation 
on physical examination, local spinal infection or other abnormality, including but not limited to 
Page 404 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 7 of 144
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled steroids 
need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded 
(topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL 
respectively.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings.  (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Page 405 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 8 of 144
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.  Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
Page 406 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 9 of 144
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the 1st dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study treatment period and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study treatment period or for 28 days after study 
drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the same 
contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing]).
Study Treatments
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets to match E2609 
will be of identical appearance.  Each subject will receive 2 tablets, which when combined will make 
up the required doses of E2609 or placebo, to be administered orally QD with food.  (revised per 
Amendment 05)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising:  

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, the 
duration of the pre-randomization phase can be extended by up to 4 weeks to allow additional 
time for resolution of the infection.)

Treatment Period (Randomization Phase):  up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Page 407 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 10 of 144
Concomitant Drug/Therapy
(revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit (see Appendix 2 for a detailed listing of 
these agents):  
Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 
Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days (whichever is 
longer) before randomization 
Live vaccines are not permitted within 3 months before randomization.  This does not apply to 
non-live/inactivated vaccines
Ig therapy and biologic drugs are not permitted within 6 months before randomization
Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization.  However, during 
the treatment period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started.  Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly.  Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset 
counts and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
(revised per Amendment 06)
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for any efficacy analyses.  
(revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  
Must be on stable dose for at least 4 weeks before randomization, except for medications that are 
administered as short courses of treatment or which are to be used intermittently as needed.  
Subjects who are on anticoagulants may have a variable dose but should have stable 
anticoagulation control for at least 4 weeks before randomization.  They may be required to stop 
their anticoagulant medication prior to CSF collection and then restart this medication after the 
LP procedure, as per local guidelines.  (revised per Amendment 04)
Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a period 
of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator, 
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
Page 408 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 11 of 144
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks
Antiplatelet therapy:  (revised per Amendment 04)
For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any other 
antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and clopidogrel (or 
any other antiplatelet drug which is not aspirin) in combination are also permitted but subjects 
who are on such a combination of antiplatelet drugs may be required to stop 1 or more of these 
antiplatelet drugs before the LP procedure and restart after the LP as per local guidelines.  
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, individually 
or in combination, are permitted.   
Assessments
Efficacy Assessments
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.  
Mini-Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing.  
International Shopping List Task:  The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
CogState Brief Battery:  A computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test.  Speed of response is the measure.

Identification – a simple choice reaction time test.  Speed of response is the measure.

One Card Back – a simple working memory test.  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
Functional Assessment Questionnaire:  The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.   The caregiver or informant provides performance ratings on 
10 complex activities of daily living performed within the preceding 4 weeks.  (revised per 
Amendment 04)  
Volumetric Magnetic Resonance Imaging:  vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood samples will be collected for the determination of the concentrations of E2609.  For subjects 
who consent to CSF sample collection, CSF samples will be collected for the determination of E2609 
concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations may be 
performed depending on emerging data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Brain atrophy will be measured by vMRI:  see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), (Aβ(1-40), total tau (t-tau), and p-tau will be measured in 
subjects who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and 
Page 409 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 12 of 144
activity in CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) may also be 
evaluated in plasma or CSF. (revised per Amendment 04)  Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will 
be approached to consider reconsenting to postrandomization CSF sample collection even if they are 
beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
(revised per Amendment 04)
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group.  (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses. (revised per Amendments 02 and 05)
Apolipoprotein E (ApoE) and N-acetyltransferase 2 (NAT2) genotyping/phenotyping will be 
conducted.  ApoE4 homozygous or heterozygous status versus non-carriers and NAT2 status will be 
used in the statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA sequence 
variability on the absorption, distribution, metabolism, and elimination of E2609, development of 
adverse events (AEs), as well as the underlying AD.  Variations in E2609 exposure or the occurrence 
of AEs observed in the study population may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and serious adverse events (SAEs), monitoring of hematology, blood chemistry, 
and urinalysis, measurement of vital signs, regular ECGs, physical and neurological examinations, 
and centralized dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a more detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the 
frequency and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the 1st month, every 2 weeks for the next 2 months 
(Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be 
monitored every 3 months until the end of the Treatment Period and at all 4 Follow-Up Visits at 2, 4, 
8, and 12 weeks after the last dose of study drug.  Serum IgG, IgA, and IgM will be monitored 
monthly for the 1st 3 months, at 6, 12, and 18 months, and at the Follow-Up Visits that occur 4, 8, 
and 12 weeks after the last dose of study drug.  (revised per Amendment 04)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
post-treatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments 
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
Page 410 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 13 of 144
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects from whom CSF samples were collected (revised per 
Amendments 02 and 04).  These samples may be tested for exploratory biomarkers associated with 
study drug or disease, or in the event that a subject develops AEs that warrant further investigation 
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected infective 
agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurologic examinations will be performed at Baseline, at 6, 12, and 18 months, and at the 4- and 
12-week Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  The neurologic examinations will include 
muscle strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Smell Identification Test, as well as other parts of the CNS. (revised per Amendment 04)
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and postscreening analysis of CSF Aβ(1-42), Aβ(1-40), 
t-tau, and p-tau will be performed using commercially available ELISAs.  (revised per 
Amendment 04)
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Page 411 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 14 of 144
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
Study Endpoints
Primary Endpoint

Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) 
and SAEs, laboratory parameters, vital signs, and ECG parameters (revised per Amendment 05) 
Secondary Endpoints 
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after at least 4 weeks and 
18 months of treatment

The population PK parameters of E2609 in CSF and plasma, including the effect of intrinsic and 
extrinsic factors (including NAT2 phenotype)  
Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
Change from baseline in:

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment 

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and during 
posttreatment follow-up

CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 18 months of treatment
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and 18 months as 
measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain amyloid 
levels

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months:  
ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
Analysis Sets 

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postdose exploratory efficacy measurement.  (revised 
per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at least 
Page 412 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 15 of 144
1 post-treatment PD measurement.
Efficacy and Biomarker Analyses (revised per Amendment 05)
Analysis for the Primary Endpoint 
There is no primary efficacy endpoint.  (revised per Amendment 05)
Analysis for the Secondary Endpoints
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 18 months.  
Data from early discontinuations will also be included. (revised per Amendment 05)
Analysis for Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) 
from 4 weeks and up to 18 months of treatment

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months 
of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 months of 
treatment, and during post-treatment follow-up

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by vMRI 

Change from baseline in left and right hippocampal, whole brain, and total ventricular volume at 
6, 12, and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid levels
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, CBB, and 
FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
Pharmacokinetic Analyses 
The PK Analysis Set will be used for E2609 concentration listings and for summaries of E2609 
concentrations in plasma and CSF by dose and day.  E2609 metabolite PK data may also be listed and 
summarized.  (revised per Amendment 05)
A population PK approach will be used to characterize the plasma PK of E2609.  For this approach, 
plasma PK data from this study will be pooled with relevant data from Phase 1 studies.  As 
appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The PK model will be 
parameterized for oral clearance (CL/F) and apparent volume of distribution (Vz/F) for E2609. 
Derived exposure parameters such as steady state area under the concentration time curve (AUC) and 
average concentration (Cavg) of E2609 and other derived parameters will be calculated from the 
Page 413 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 16 of 144
model using the individual estimates parameterized for oral clearance and dosing history. (revised 
per Amendment 04)
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma 
biomarkers, MRI endpoints).  The percentage change from baseline in CSF Aβ(1-x), Aβ(1-40), 
Aβ(1-42), t-tau, p-tau, and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months will be analyzed and presented graphically.  (revised per Amendments 04 and 05)  
Baseline levels and changes in t-tau and p-tau will be correlated with changes in CSF Aβ(1-42), 
imaging markers, and ApoE4 status.  Summary statistics for CSF biomarkers will be assessed for 
evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI and E2609 
dose, plasma and CSF exposure will be initially explored graphically and any emergent relationship 
will be explored through population PK/PD modeling.  Additionally, the relationship between CSF 
exposure to E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  (revised per Amendments 04 and 05)
Additionally, the relationship between plasma exposures of E2609 and select lymphocyte parameters 
will be explored graphically, and any emergent relationship will be explored using population-based 
modeling methods. (revised per Amendment 04)
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, vital sign measurements, and cognitive decline 
assessment such as CBB will be summarized by treatment group using descriptive statistics.  (revised 
per Amendment 05)
Lymphocyte Subsets
Lymphocyte subsets, including but not limited to, CD4 [T helper cells], CD8 [cytotoxic T cells], 
CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells 
will be summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets 
and the mean change from baseline in lymphocyte subsets will also be displayed graphically over 
time by dose.  
Serum IgG, IgM, IgA will be measured and summarized in the same manner as other laboratory 
parameters. (revised per Amendment 04)
Page 414 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 17 of 144
Interim Analyses
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and 
perform interim analyses of these data.  Investigators, other clinical site staff, subjects,  
caregivers/informants and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when 60 subjects (±20%) have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)
Stratification
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no).  (revised per Amendment 01)
Sample Size Rationale
A total of 15 subjects per dose is deemed sufficient to derive adequate safety and PK/PD data to aid 
in the selection of appropriate doses and the design of the Phase 3 studies that may be planned 
subsequently.  (revised per Amendment 04)  Based upon the selection of the E2609 50-mg dose for 
the Phase 3 studies, subjects randomized to the active treatment arms will be re-assigned to the 
selected 50-mg dose for further evaluation. (revised per Amendment 06)
Page 415 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 18 of 144
3
TABLE OF CONTENTS
REVISION HISTORY .....................................................................................................i
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................23
5
ETHICS.......................................................................................................................26
5.1
Institutional Review Boards/Independent Ethics Committees.............................26
5.2
Ethical Conduct of the Study..............................................................................26
5.3
Subject Information and Informed Consent ........................................................27
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................29
7
INTRODUCTION.......................................................................................................30
7.1
Results of Interim Evaluations ...........................................................................31
7.2
Nonclinical and Clinical Safety Data..................................................................31
8
STUDY OBJECTIVES................................................................................................34
8.1
Primary Objective ..............................................................................................34
8.2
Secondary Objectives.........................................................................................34
8.3
Exploratory Objectives.......................................................................................34
9
INVESTIGATIONAL PLAN ......................................................................................36
9.1
Overall Study Design and Plan...........................................................................36
9.1.1
Prerandomization Phase ...........................................................................38
9.1.1.1
Screening Period...............................................................................39
9.1.1.2
Baseline Period.................................................................................41
9.1.2
Randomization Phase ...............................................................................41
9.1.2.1
Treatment Period ..............................................................................42
9.1.2.2
Early Discontinuation .......................................................................42
9.1.2.3
Follow-Up Period .............................................................................42
9.2
Discussion of Study Design, Including Choice of Control Groups......................42
9.2.1
Overview..................................................................................................42
9.2.2
Rationale for Study Population.................................................................43
9.2.3
Rationale for Clinical Endpoints...............................................................44
9.2.4
Rationale for Biomarkers..........................................................................45
9.2.4.1
Overall Rationale..............................................................................45
9.2.4.2
Soluble Biomarkers in CSF...............................................................45
9.2.4.3
Amyloid PET....................................................................................46
9.2.4.4
vMRI................................................................................................46
9.2.5
Clinical Risks and Mitigation Strategy......................................................48
Page 416 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 19 of 144
9.3
Selection of Study Population ............................................................................49
9.3.1
Inclusion Criteria......................................................................................49
9.3.2
Exclusion Criteria.....................................................................................51
9.3.3
Removal of Subjects from Therapy or Assessment ...................................55
9.4
Treatments.........................................................................................................58
9.4.1
Treatments Administered..........................................................................58
9.4.2
Identity of Investigational Product............................................................59
9.4.2.1
Chemical Name and Formula of E2609.............................................59
9.4.2.2
Comparator Drug..............................................................................59
9.4.2.3
Labeling for Study Drug ...................................................................59
9.4.2.4
Storage Conditions ...........................................................................60
9.4.3
Method of Assigning Subjects to Treatment Groups.................................60
9.4.4
Selection of Doses in the Study ................................................................60
9.4.5
Selection and Timing of Dose for Each Subject........................................62
9.4.6
Blinding ...................................................................................................62
9.4.7
Prior and Concomitant Therapy................................................................63
9.4.8
Treatment Compliance .............................................................................65
9.4.9
Drug Supplies and Accountability ............................................................65
9.5
Study Assessments.............................................................................................67
9.5.1
Assessments .............................................................................................67
9.5.1.1
Demography.....................................................................................67
9.5.1.2
Baseline Assessments .......................................................................67
9.5.1.2.1
Medical History and Physical Examinations................................67
9.5.1.2.2
Viral Testing...............................................................................67
9.5.1.2.3
B12 Testing ................................................................................67
9.5.1.2.4
TB Exposure Testing ..................................................................68
9.5.1.2.5
Urine Drug Testing .....................................................................68
9.5.1.3
Efficacy Assessments .......................................................................68
9.5.1.3.1
Psychometric Assessments..........................................................68
9.5.1.3.2
Volumetric MRI..........................................................................70
9.5.1.3.3
Cerebrospinal Fluid Sampling.....................................................70
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................70
9.5.1.4.1
Pharmacokinetic Assessments.....................................................70
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments................................................................................71
9.5.1.5
Safety Assessments...........................................................................73
9.5.1.5.1
Adverse Events and Events Associated With Special Situations..73
Page 417 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 20 of 144
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................76
9.5.1.5.3
Laboratory Measurements...........................................................77
9.5.1.5.4
Vital Signs and Weight Measurements........................................79
9.5.1.5.5
Physical Examinations ................................................................79
9.5.1.5.6
Electrocardiograms .....................................................................79
9.5.1.5.7
Safety MRI .................................................................................80
9.5.1.5.8
Dermatologic Assessment ...........................................................81
9.5.1.5.9
Neurologic Examination .............................................................81
9.5.1.5.10 Pregnancy Test ...........................................................................81
9.5.1.5.11 Columbia Suicide Severity Rating Scale .....................................82
9.5.1.5.12 Biomarker Samples.....................................................................82
9.5.1.5.13 Ophthalmic Examinations ...........................................................82
9.5.2
Schedule of Procedures/Assessments........................................................82
9.5.2.1
Schedule of Procedures/Assessments................................................82
9.5.2.2
Description of Procedures/Assessments Schedule .............................91
9.5.3
Appropriateness of Measurements............................................................92
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................92
9.5.4.1
Reporting of Serious Adverse Events................................................92
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding....................................................................................93
9.5.4.3
Reporting of Events Associated with Special Situations....................94
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................94
9.5.4.3.2
Reporting of Study-Specific Events.............................................94
9.5.4.4
Expedited Reporting .........................................................................94
9.5.4.5
Breaking the Blind............................................................................95
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................95
9.5.5
Completion/Discontinuation of Subjects...................................................95
9.5.6
Abuse or Diversion of Study Drug............................................................96
9.5.7
Confirmation of Medical Care by Another Physician................................96
9.6
Data Quality Assurance......................................................................................96
9.6.1
Data Collection.........................................................................................96
9.6.2
Clinical Data Management .......................................................................97
9.7
Statistical Methods.............................................................................................97
9.7.1
Statistical and Analytical Plans.................................................................97
9.7.1.1
Study Endpoints................................................................................97
Page 418 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 21 of 144
9.7.1.1.1
Primary Endpoint........................................................................97
9.7.1.1.2
Secondary Endpoints...................................................................97
9.7.1.1.3
Exploratory Endpoints ................................................................98
9.7.1.2
Definitions of Analysis Sets..............................................................98
9.7.1.3
Subject Disposition...........................................................................98
9.7.1.4
Demographic and Other Baseline Characteristics..............................99
9.7.1.5
Prior and Concomitant Therapy ........................................................99
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05)......100
9.7.1.6.1
Primary Efficacy Analysis.........................................................100
9.7.1.6.2
Secondary Efficacy Analyses....................................................100
9.7.1.6.3
Exploratory Efficacy Analyses..................................................100
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................101
9.7.1.7.1
Pharmacokinetic Analyses ........................................................101
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ...................................................................................101
9.7.1.8
Safety Analyses ..............................................................................102
9.7.1.8.1
Extent of Exposure....................................................................102
9.7.1.8.2
Adverse Events.........................................................................102
9.7.1.8.3
Laboratory Values.....................................................................104
9.7.1.8.4
Vital Signs ................................................................................105
9.7.1.8.5
Electrocardiograms ...................................................................105
9.7.1.8.6
Other Safety Analyses...............................................................105
9.7.2
Determination of Sample Size ................................................................106
9.7.3
Interim Analysis.....................................................................................106
9.7.4
Other Statistical/Analytical Issues ..........................................................106
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................106
10
REFERENCE LIST...................................................................................................107
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....111
11.1
Changes to the Protocol....................................................................................111
11.2
Adherence to the Protocol................................................................................111
11.3
Monitoring Procedures.....................................................................................111
11.4
Recording of Data............................................................................................112
11.5
Identification of Source Data............................................................................112
11.6
Retention of Records........................................................................................113
11.7
Auditing Procedures and Inspection .................................................................113
11.8
Handling of Study Drug ...................................................................................113
11.9
Publication of Results ......................................................................................114
Page 419 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 22 of 144
11.10 Disclosure and Confidentiality .........................................................................114
11.11 Discontinuation of Study..................................................................................114
11.12 Subject Insurance and Indemnity......................................................................115
12
APPENDICES...........................................................................................................116
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts ................56
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.................................................................................................57
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline........................................................................61
Table 4
Clinical Laboratory Tests........................................................................78
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™................................79
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) ......................................................................83
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20)..............................................................86
Table 8
Summary of Blood and CSF Sample Volumes........................................91
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202..........................................................37
Figure 2
Assessments to be Performed at Screening by Tier .................................40
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.............................................116
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications..........119
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 132
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential .....................135
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach.................................138
Page 420 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 23 of 144
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg,
1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta (β)-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carboxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
Page 421 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 24 of 144
Abbreviation
Term
ED
early discontinuation
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
Page 422 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 25 of 144
Abbreviation
Term
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 423 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 26 of 144
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 424 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 27 of 144

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 425 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 28 of 144
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for from 4 weeks and up to 18 months 
(or at Early Discontinuation).  This consent for CSF sample collection is not required for 
study eligibility. (revised per Amendments 02 and 05)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects and will be via a 
separate, optional CSF consent form for the study.  (revised per Amendment 04)
Page 426 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 29 of 144
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 35 investigational sites in the United States.
(revised per 
Amendments 01, 02, 04, and 05)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 427 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 30 of 144
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010;
Lu, et al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, 
thus accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Rosen, et al., 1984; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study is a Phase 2 study for the E2609 program, and is designed to 
establish safety
in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol) and in subjects with mild to moderate AD.  (revised per Amendment 05)  Results 
from this study will guide both the decision to move into Phase 3 development and the 
selection of the dose strengths to be taken into Phase 3.    
Page 428 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 31 of 144
In the MCI/Prodromal and mild to moderate AD population, this study will compare placebo 
and 3 oral doses of E2609 (5, 15, and 50 mg) administered once daily (QD) for 18 months.  
(revised per Amendment 05)  
This study will include interim evaluations of the pharmacokinetic (PK), pharmacodynamic 
(PD), safety, and tolerability of chronic dosing with E2609. (revised per Amendment 05)  
Furthermore, there will be close monitoring of safety by an independent data safety 
monitoring board (DSMB), including a formal safety review as soon as the randomized 
subjects (n=60, ±20%) have completed at least 12 weeks of treatment, have discontinued 
study drug or have withdrawn from the study.  (revised per Amendments 04 and 05) The 
study also includes a number of exclusion criteria, specific blinded safety monitoring 
procedures and safety criteria for discontinuation of study drug in light of the preclinical and 
clinical safety data collected to date following administration of E2609.  
7.1
Results of Interim Evaluations
(revised per Amendment 06)
Unblinded interim evaluations of the safety and tolerability of E2609 suggested favorable 
safety at all doses of E2609.  Additionally, analyses of the PD effects (reduction from 
baseline in CSF Aβ levels) of E2609 5, 15, and 50 mg per day have indicated that  E2609 
50 mg per day produced relatively high levels of CSF Aβ reduction (greater than 50%).  
Based on the results of these analyses, E2609 50 mg per day has been selected as the dose for 
Phase 3 development. 
As E2609 5 and 15 mg per day will not be advanced clinically, subjects initially randomized 
to the E2609 5 and 15 mg per day treatment arms will be re-assigned in a blinded manner to 
the E2609 50 mg treatment arm provided that they will have at least 12 weeks of treatment 
remaining in the Randomization Phase.  The purpose of this dose re-assignment is to further 
characterize the safety and tolerability of E2609 50 mg.  
7.2
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
Page 429 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 32 of 144
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the PK levels of E2609 and the PD effects on BACE
activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
Page 430 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 33 of 144
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 431 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 34 of 144
8
STUDY OBJECTIVES
8.1
Primary Objective
(revised per Amendment 05)
The primary objective is:  

To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendments 02 and 05)

To characterize the plasma and CSF PK of E2609 

To assess the effects of E2609 on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and at 
18 months of treatment 
8.3
Exploratory Objectives
(revised per Amendments 01,02, 04, and 05)  
The exploratory objectives are:  

To explore the effects of E2609 compared on CSF Aβ(1-40) and BACE1 measurements 
from 4 weeks and up to 18 months of treatment 

To explore the effects of E2609 compared with placebo on various biomarkers.  
Biomarkers to be explored may include, but not limited to:  
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment (revised per Amendment 06)
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up by assessment 
of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
Page 432 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 35 of 144
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of E2609 on measured clinical 
efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF amyloid 
isoforms, brain amyloid, and vMRI 

To explore relationships between both E2609 dose and exposure, with PD and safety 
endpoints 
Page 433 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 36 of 144
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists
of 2 phases: 
Prerandomization and Randomization.  The 
Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
All subjects (MCI/Prodromal and mild to moderate AD) will initially be randomized 1:1:1:1 
to 4 treatment groups (5, 15, or 50 mg E2609 or placebo) (revised per Amendments 01 and 
05).  Upon implementation of Amendment 06, at the next regularly scheduled visit, subjects 
receiving E2609 5 or 15 mg who have not yet completed Visit 17 (Week 66), will be 
re-assigned in a blinded manner to E2609 50 mg for the remainder of the treatment period.  
In order to maintain the blind, all subjects who have not yet had Visit 17 will go through the 
same procedures with the placebo-randomized subjects continuing to receive placebo and 
those randomized to E2609 50 mg continuing to receive 50 mg.  (revised per Amendment 06)
An overview of the study design is presented in Figure 1.
Page 434 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 37 of 144
Figure 1
Design of Study E2609-G000-202
(revised per Amendments 01, 02, 05, and 06)
R = randomization, AD = Alzheimer’s Disease, MCI = mild cognitive impairment.
This study will be limited to approximately 35 sites in the United States, with approximately 
60 (±20%) eligible subjects randomized at Visit 3, 1:1:1:1 to 4 treatment groups within each 
clinical cohort.  In addition to the placebo group, 3 doses of E2609 will be used to reduce 
CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, 
respectively, at steady state.  PK/PD modeling shows these doses should achieve these 
targets when administered QD with food and will be evaluated based on the 4-week (or later) 
assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement (see Section 9.4.4 ). (revised per Amendments 01, 02, 04, and 05) Safety data 
will be monitored in a blinded fashion on a regular basis.  
In addition, approximately every 3 months from the time the 1st subject is randomized into
the study through the time the last subject is randomized, an independent DSMB (including 
at least 1 immunologist) will review all safety data in an unblinded manner. (revised per 
amendment 06) The DSMB will make recommendations to Eisai after each review as to 
whether any change(s) to the study are necessary.  (revised per Amendments 01, 04, and 05)  
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
Page 435 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 38 of 144
treatment.  (revised per Amendment 05)  Refer Section 9.7.3 for more detail.  These data will 
be used to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions 
from baseline in CSF Aβ(1-x) levels (see Section 9.4.4). The median and mean percentage 
change from baseline in CSF Aβ(1-x) measured after 4 weeks or more of treatment for each 
dose of E2609 and the 90% confidence interval (CI) for the median will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data and will relate the average steady state plasma concentration of 
E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline determined after at 
least 4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug 
early), an interim safety analysis will be conducted by Eisai and the DSMB.  (revised per 
Amendments 01, 04, and 05)  At the completion of this interim safety review, the frequency 
of subsequent unblinded safety reviews will be re-evaluated by the DSMB and the Sponsor
and this information will be provided in the DSMB charter. (revised per Amendment 06) 
Subjects will continue study drug while the DSMB reviews all the available safety data.  
(revised per Amendment 05)  At the time of this interim safety analysis, some subjects will 
have more than 12 weeks of safety data.  
Interim analyses are planned and are discussed in Section
9.7.3.
(revised per 
Amendment 03)
Based on the results of the interim analyses, the E2609 50 mg dose has been chosen as the 
clinical dose for the Phase 3 studies.  In order to collect additional safety data for E2609 
50 mg, subjects randomized to E2609 5 or 15 mg in this study will be re-assigned to E2609 
50 mg if and only if these subjects have at least 12 weeks of treatment remaining in the 
Randomization Phase following study drug dose re-assignment.  Therefore, subjects who 
completed Visit 17 assessments prior to the implementation of Amendment 06 will remain 
on their original randomized dose.  As study drug dose re-assignment will occur in a blinded 
manner, a 4-week interim safety assessment following study drug re-assignment will be 
required for all subjects.  (revised per Amendment 06)
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Page 436 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 39 of 144
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization, the clinician will provide a judgment on the classification of a subject as 
either MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This 
judgment may be discussed and reviewed with the Sponsor or Sponsor’s representative, as 
necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Page 437 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 40 of 144
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 438 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 41 of 144
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination (including 
the Brief Smell Identification Test [Sensonics Inc.]) will be performed.  (revised per 
Amendment 04) A urine pregnancy test will be conducted for females of childbearing 
potential.  Blood will be collected from all subjects for clinical chemistry and hematology, 
lymphocyte subset analyses, Ig analyses, and PD assessments.  Blood samples will be 
collected and stored for determination of a subject’s previous exposure to infective pathogens 
in the event of AEs that warrant further investigation occurring at a later point in the study.  
Psychometric assessments will be administered to the subject in the order stated in Table 6.  
The caregiver or informant needs to be present at this visit.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, a CSF sample will be obtained at this 
visit for PK and PD assessments (see Section 9.5.1.4).  (revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the N-acetyltransferase 2 (NAT2) phenotype of subjects 
enrolled in the study (see Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
Page 439 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 42 of 144
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  (revised per Amendment 06)
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug.  (revised 
per Amendments 04 and 05)  
9.1.2.3
Follow-Up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 4 posttreatment Follow-Up Visits: 2, 4, 8, and 
12 weeks after the last dose of study drug.  If clinically indicated, more frequent safety 
assessments can be conducted as part of unscheduled visits during the post-treatment 
Follow-Up Period.  (revised per Amendment 04)
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Apr 2018.  (revised 
per Amendment 05)

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The primary objective of the study is to assess the safety and tolerability of daily dosing with 
E2609 in subjects with MCI/Prodromal AD and in subjects with mild to moderate AD. 
Immunological and hematological parameters will also be assessed.  (revised per 
Amendment 04)  
Page 440 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 43 of 144
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
Secondary endpoints include CSF PK and plasma PK parameters of E2609 based on 
population PK analysis and the percentage reduction of Aβ(1-x) and Aβ(1-42) in CSF 
relative to baseline from 4 weeks and up to 18 months of treatment.
The intrinsic and 
extrinsic factors on the PK characteristics will also be explored.
Exploratory endpoints include CSF Aβ(1-40) and BACE1 measures as well as CSF 
biomarkers of neuronal degeneration (eg, t-tau and p-tau), volumetric MRI measurements, 
plasma amyloid measurements, brain amyloid levels as measured by amyloid PET and 
clinical assessments.  (revised per Amendment 05) Exploratory endpoints including 
assessments of efficacy, safety, and other biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups (Section 9.7.4)  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
Page 441 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 44 of 144
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 
2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for Clinical Endpoints
The 14-item version of the ADAS-Cog will be used in the present study since it is considered 
more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975)
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable 
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
Page 442 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 45 of 144
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment. 
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living.  The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  Volumetric magnetic resonance imaging is discussed in 
Section 9.2.4.4.
9.2.4
Rationale for Biomarkers
9.2.4.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (t-tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.4.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
Page 443 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 46 of 144
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both t-tau and p-tau are sensitive markers of axonal and neuronal degeneration (t-tau) and 
neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel with 
disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have been 
correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful predictors 
of cognitive decline and progression to dementia due to AD.  Rebalancing dysregulated 
amyloid production early in the process may positively affect the neurodegenerative process 
and thus affect these markers and benefit the disease trajectory.  Therefore, monitoring these 
markers in conjunction with amyloid imaging may provide further supportive evidence of 
disease modifying effects.  (revised per Amendment 04)
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.4.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted on subjects with Screening PET scans performed for this study 
(ie, historical scans cannot be used for the longitudinal analyses). (Revised per Amendments
02 and 05)
9.2.4.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
regions during the early stages of disease and progresses towards the anterior regions of the 
Page 444 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 47 of 144
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF t-tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Page 445 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 48 of 144
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.5
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and percentage 
change from baseline), skin rash, reoccurrence of herpes virus infections including any 
oral herpes, genital herpes or shingles, other infections, MRI changes, ECGs, and 
pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be 
questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and post-treatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
Page 446 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 49 of 144
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood and DNA samples will be taken and stored for all subjects, 
and CSF samples will be taken and stored for all subjects who consent to CSF sample 
collection (revised per Amendment 02).  These samples may be tested in the event that a 
subject develops AEs that warrant further investigation (eg, if a subject develops a 
treatment-emergent infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Treatment Period, and at the final Follow-Up Visit.

Full neurologic examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  Details of the neurologic
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using the 
detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, Baseline,
and at regular intervals during the Treatment and Follow-Up
Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 4 off-treatment Follow-Up visits 
(2, 4, 8, and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated. (revised per Amendment 04)

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Approximately 60 (±20%) eligible MCI/Prodromal or mild to moderate AD subjects will be 
randomized at approximately 35 sites in the United States (revised per Amendments 02 and 
04).  There will be no restriction to the number of subjects from either population.  
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
Page 447 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 50 of 144
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Required at Screening Visit 1:  
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
Page 448 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 51 of 144
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
Page 449 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 52 of 144
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
Page 450 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 53 of 144
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Page 451 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 54 of 144
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.

(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).  (revised per Amendment 04)
Page 452 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 55 of 144
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (see 
Section 9.1.2.3). (revised per Amendments 04 and 05)
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test but who 
has no clinical signs or symptoms of infection, will have study drug temporarily 
suspended for at least 2 weeks but no more than 4 weeks.  During this period of study 
drug suspension, lymphocyte subset counts and complete blood count (CBC) with 
differentials will continue to be tested weekly until CD4 (T helper cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) have all returned to greater than the population-adjusted 
LLN after which time study drug can be resumed.  Testing of lymphocyte subset counts 
and CBC with differentials is required weekly for 4 weeks following resumption of study 
drug administration.  Temporary suspension and rechallenge with study drug is only 
permitted once for any given subject.  If the lymphocytes and CD counts do not return to 
greater than the population-adjusted LLN within 4 weeks from the start of temporary 
suspension the subject will need to be permanently discontinued from study drug.  
(revised per Amendment 04)
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendments 02 
and 04)  During the early stages of the treatment period, where visits are conducted 
weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already scheduled to be 
Page 453 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 56 of 144
measured on a weekly basis and so additional visits or blood draws are not required.  
(revised per Amendment 02)  For these subjects, the decision as to whether the subject 
remains on study drug or is to be discontinued from study drug will be based upon 
clinical judgment and will take into account any clinical presentation in addition to the 
lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue, 
discontinue, or temporarily 
suspend study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts below 
discontinuation threshold and no clinical signs 
or symptoms of infection
Retest within 1 week along 
with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
temporarily suspend study 
drug for between 2 and 
4 weeks.  Continue weekly 
testing of lymphocyte subsets 
and CBC with differentials.  
Rechallenge with study drug 
allowed when CD4 (T helper 
cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) 
absolute counts all greater 
than population-adjusted 
LLN.  Temporary suspension 
and rechallenge permitted 
only once for each subject.
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold
Lymphocyte subset counts 
(and CBC with differentials) 
to be performed weekly until 
lymphocyte subset counts 
return to ≥ population-
adjusted LLN 
Decision will be based upon 
lymphocyte subset counts 
and clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  
(Table revised per Amendments 02 and 04)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
Page 454 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 57 of 144
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds, subjects with infections of moderate intensity will be 
discontinued from study drug (eg, subjects whose infections are not localized, or subjects 
who are systemically unwell, or who require systemic anti-infective drug treatment).   All 
subjects with infection who are discontinued from study drug will be followed for a 
period of 12 weeks or until the infection resolves/ stabilizes or until the CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have returned to 
greater than population-adjusted LLN (whichever comes latest).
(revised per 
Amendments 02 and 04)
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts below 
discontinuation threshold
If confirmed with 
repeat testing within 
1 week, then 
temporarily suspend 
study drug as per 
instructions above.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts between 
population-adjusted LLN and 
discontinuation threshold 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts always >
population-adjusted LLN 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  
(Table revised per Amendments 02 and 04)
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
Page 455 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 58 of 144
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 2, 4, 8, and 12 weeks after the last 
dose of study drug.  They will also undertake an Unscheduled Visit (with MRI) at 
approximately 4 weeks after the visit at which such MRI features were first identified.  
An MRI will also be performed at approximately the time of the final Follow-Up Visit
(Visit 20).  Additional visits for safety may be arranged if clinically indicated in the 
opinion of the investigator, including after 12 weeks after the last dose of study drug.  At 
any time during the treatment period, subjects who have asymptomatic, treatment-
emergent microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found. They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
(revised per Amendment 04)
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered are 5, 15, and 50 mg E2609 or placebo prior to the 
implementation of Amendment 06, and 50 mg E2609 or placebo after the implementation of 
Amendment 06 as shown in Figure 1.  (revised per Amendments 01, 05, and 06)  Study 
treatment will begin on Day 1 (at the study site) following Randomization and will continue 
for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for specific
information on drug administration on days when PK sampling is to be performed.
Page 456 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 59 of 144
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5, 15, 50 mg, or placebo.  The tablets 
will be supplied by the Sponsor in labeled blister packs.  The product release certificates for 
E2609 and placebo will be included in the clinical study report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only
Page 457 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 60 of 144

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups are 
described in Section 9.4.1. (revised per Amendments 01 and 05)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, initial doses will be selected such that at steady state, they will result 
in 25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of 
PD effects.  (revised per Amendment 06)
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study 
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Page 458 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 61 of 144
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma 
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1 
Activity
% Reduction 
CSF A(1-x)
5 
6.2
3.3
80.3
16.2
33
15 
18.6
10
240.9
36.6
56
50 
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = beta-amyloid converting enzyme, CSF = cerebrospinal fluid, Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from 
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1 
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013). Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients.  (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 
400 mg (17.3% decrease).  No subject had infections or drug rash while receiving E2609 
100 mg QD or at lower doses in Study 002, whereas at 200 and 400 mg QD, 4 subjects had 
symptomatic orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The 
highest dose for Study 202 of 50 mg QD (tablet administered with food) is therefore 
expected to have a similar or better safety profile compared with the 100 mg QD capsule 
(administered fasted) in Study 002.  Specific exclusion criteria, blinded and unblinded safety 
monitoring procedures, and safety criteria for discontinuation from study drug are included in 
this study in order to mitigate any immunology-related risk with E2609, particularly in light 
of the progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
treatment.  These interim analyses, as well as analyses of safety data, will be performed on an 
ongoing basis.  Refer Section 9.7.3 for more detail. The median and mean percentage change 
from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of E2609 
and its 90% confidence interval for the median will be derived.  In addition, exploratory 
PK/PD modeling will be conducted.  This PK/PD modeling will use the observed PK and PD 
Page 459 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 62 of 144
data and will relate the average steady state plasma concentration of E2609 to steady state 
CSF Aβ(1-x) percentage reduction from baseline after at least 4 weeks of dosing.  (revised 
per Amendments 01, 02, 03, 04, and 05)
Unblinded interim analyses have indicated E2609 50 mg per day produced relatively high 
levels of CSF Aβ reduction (greater than 50%) with an acceptable safety profile.  As a result, 
E2609 50 mg has been selected as the dose for Phase 3 development.  To gain a more 
comprehensive safety and tolerability profile of E2609 50 mg, subjects randomized to E2609 
5 and 15 mg will be re-assigned to E2609 50 mg for the remaining of the 18-month treatment 
period with the provision that they will have at least 12 weeks of treatment remaining in the 
Randomization Phase.  (revised per Amendment 06)
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects, caregivers/informants, and 
all clinical site personnel involved with the conduct and interpretation of the study, including 
investigators will be blinded to the treatment codes (double-blind).  In order to make 
decisions about the remainder of the study as well as the full E2609 clinical development 
program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and perform 
interim analyses of these data.  (revised per Amendment 03)  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
The PK/PD interim analyses will take place throughout the study as per Amendment 03 and 
will be conducted by an independent PK/PD scientist at the sponsor.  Any additional changes 
to dose required for this study will be reflected in a further amendment to the protocol and 
the Statistical Analysis Plan will detail how data will be handled in the primary analysis. 
(revised per Amendments 02 and 04)
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
Page 460 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 63 of 144
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1 through Listing 5.  Medications that are permitted with 
restrictions are listed in 6 through Listing 8. (revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  (revised per 
Amendment 04)

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization
Page 461 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 64 of 144

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization.  However,
during the treatment period of the study, short term (not more than 14 days) use of 
steroids up to the equivalent of prednisolone 40 mg once daily is permitted after 
discussion with the Medical Monitor. Dosing with study drug should be suspended from 
the time steroid treatment is started. Complete blood count and lymphocyte subsets 
should be determined prior to starting steroid treatment and continue to be monitored 
weekly. Study drug may be resumed after discussion with the Medical Monitor when the 
following conditions are met: (1) treatment with steroids has been completed for at least
1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte 
subset counts and CBC with differentials is required for 4 weeks following resumption of 
study drug administration.  (revised per Amendment 04)

(revised per Amendment 06)
Subjects who initiate treatment with an AChEI or memantine during the study, or who
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for any 
efficacy analyses.  (revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed.  Subjects who are on anticoagulants may have a variable dose but should have 
stable anticoagulation control for at least 4 weeks before randomization. They may be 
required to stop their anticoagulant medication prior to CSF collection and then restart 
this medication after the LP procedure, as per local guidelines.  (revised per 
Amendment 04)

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.    (revised per Amendment 05)
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any 
other antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and
clopidogrel (or any other antiplatelet drug which is not aspirin) in combination are also 
permitted but subjects who are on such a combination of antiplatelet drugs may be 
Page 462 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 65 of 144
required to stop 1 or more of these antiplatelet drugs before the LP procedure and restart 
after the LP as per local guidelines.   

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, are permitted.   
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Page 463 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 66 of 144
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study 
drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator (or if regionally required, the head of the medical institution or the 
designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
Page 464 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 67 of 144
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6 and 
Table 7.  A complete physical examination will include evaluations of the head, eyes, ears, 
nose, throat, neck, chest (including heart and lungs), abdomen, limbs, and skin, and a 
neurological examination (including the Brief Smell Identification Test [Sensonics Inc.]). 
(revised per Amendment 04).  A urogenital examination will only be required in the presence 
of clinical symptoms related to this region.  Documentation of the physical examination will
be included in the source documentation at the site.  Significant findings at the Screening 
Visit will be recorded on the Medical History and Current Medical Conditions eCRF.  
Changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
Page 465 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 68 of 144
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  At the Screening Visit, the recommended order of 
assessments is: MMSE, ISLT (immediate recall), CBB, ISLT (delayed recall), CBB (repeat 
CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the 
assessments are to be conducted in the following order: MMSE, CDR, ADAS-cog14, FAQ,
ISLT (immediate recall), CBB, and ISLT (delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
Alzheimer's Disease Assessment Scale - cognitive subscale:  Discussed in Section 9.2.3.  
(revised per Amendment 05)
Clinical Dementia Rating:  The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
ISLT:  The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects will read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
CogState Brief Battery:  The CBB is a computer-based battery comprising 4 cognitive tests:  
Page 466 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 69 of 144

Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.

Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.

One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
Functional Assessment Questionnaire: The caregiver or informant provides performance 
ratings (from 0 to 3) on 10 complex activities of daily living performed within the preceding 
4 weeks.  Scores range from 0 (independent) to 30 (dependent).  (revised per Amendment 04)
Page 467 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 70 of 144
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of E2609.  For 
subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of E2609 concentrations. 
(revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with E2609.
Page 468 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 71 of 144
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A 2nd PK blood sample will be collected as close as possible in time to the 
LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the 1st report of an SAE or severe unexpected AE 
and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal (Section 9.5.1.3.3).  The timing of the Baseline LP needs 
to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization 
timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  (revised per Amendment 04)  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 levels and activity.  (revised per 
Amendment 04)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
Page 469 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 72 of 144
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses.  Aβ(1-x) in both CSF and plasma will be measured using a modified 
commercially available enzyme-linked immunosorbent assay (ELISA).  The pre- and 
postscreening analysis of CSF Aβ(1-42), Aβ(1-40), t-tau, and p-tau will be performed using 
commercially available ELISAs.  (revised per Amendment 04)  BACE1 levels will be 
measured using internally developed fluorescence resonance energy transfer and ELISA 
based assay(s).  Substrates of BACE1 inhibition may also be explored using Western blots or 
other amenable methodology if clinical observations warrant and if analytes can be reliably 
tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
For subjects who consented to CSF sample collection, CSF samples from the Baseline Visit 
will also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, 
but not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, 
or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
Page 470 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 73 of 144
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of treatment (or at ED, providing the subject has received at least 
39 weeks of study drug).  Longitudinal amyloid PET imaging will only be conducted on 
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses) (Table 6).  (revised per Amendments 02 and 05)  PET 
scanning will be performed with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and post-treatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
Page 471 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 74 of 144
whether or not considered related to the investigational product (Note:  It is not necessary 
to report every sign or symptom as a separate AE if the overall disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, discontinuation of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).    Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition eCRF.  SAEs will be collected for 3 months after the 
last dose of study drug, ie, through to the final Follow-Up visit (Visit 20).  However, any 
SAEs volunteered by subjects after this time point must be reported according to standard 
procedures.  (revised per Amendments 04 and 05)
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADAS-cog14, MMSE, ISLT and CBB (see 
Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment Period, 
and if this cognitive decline is considered by the investigator to be excessive relative to the 
subject’s recent AD history, this finding should be reported as an AE.  
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  
Page 472 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 75 of 144

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following AEs will require the collection of information sufficient to provide a detailed 
description of the event, treatment and outcome to the Medical Monitor for the study: any 
treatment-emergent significant laboratory abnormality; any seizures, herpes zoster infection, 
severe infection; any moderate to severe drug rash or any rash lasting more than 72 hours 
(regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the final Follow-Up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. (revised per Amendment 04)
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Page 473 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 76 of 144
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
Page 474 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 77 of 144
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Page 475 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 78 of 144
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening and Baseline only)  (revised per Amendment 02)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte T and B cell subset analyses (see Table 5).  Regulatory T cells (revised per 
Amendment 04)
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HbsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (including but not limited to CD3, CD4, CD8, CD45, CD19, 
CD16, CD56, and CD14) and total lymphocyte counts will be measured in order to provide 
the lymphocyte subset data as shown in Table 5.  In addition, Regulatory T cells will be 
measured.  Current sponsor data supports the literature showing there is an age-related 
decline in lymphocyte subsets (see Appendix 5). These data have been used to revise the 
LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts 
to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively) (revised per 
Amendments 02 and 04).  
Page 476 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 79 of 144
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
(Table 5 revised per Amendment 04)
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
Page 477 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 80 of 144
in the supine position for at least 5 minutes.
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2 Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, and 18 and at the final Follow-Up Visit 
(Visit 20).  (revised per Amendment 04) In the event of an Unscheduled Visit, the 
investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already 
performed during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and 4 Follow-Up Visits at 2, 4, 8 and 12 weeks 
after the last dose of treatment.  (revised per Amendment 04) Subjects will also undertake an 
Page 478 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 81 of 144
Unscheduled Visit (with MRI) at approximately 30 days after the visit at which such MRI 
features were first identified.  Additional visits may be arranged if clinically indicated in the 
opinion of the investigator, and may occur later than 12 weeks after the final dose of study 
drug.
9.5.1.5.8
DERMATOLOGIC ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGIC EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve; the Brief Smell Identification Test (Sensonics 
Inc.) will be administered at the same visits to objectively test olfaction.  Treatment-emergent 
abnormal neurological findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 479 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 82 of 144
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes. The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 480 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 83 of 144
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary)a
X
X
Demographics
X (Tier 1)
Medical historyb
X (Tier 1)
Prior / concomitant medicationsc
X (Tier 1)
X
Vital signs including weightd
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTe
X (Tier 1)
X
MMSEe
X (Tier 1)
X
CDRe
X (Tier 1)
X
FAQe
X (Tier 1)
X
ADAS-cog14
e
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGf
X (Tier 2)
X
Blood and urine for clinical laboratory testsg
X (Tier 2)
X
Blood for lymphocyte subset analysesh
X (Tier 2)
X
Blood for Ig analysesi
X (Tier 2)
X
Blood for viral screenj
X (Tier 2)
Blood for thyroid function testsk
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIl
X (Tier 3)
Amyloid PET scanm
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagea
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
(Table revised per Amendments 02 and 04)
Page 481 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 84 of 144
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
Subjects who initially consented to CSF collection and provided a baseline CSF sample but did not provide a 
postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample collection 
even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
For those subjects who do consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or 
at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to 
be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each individual subject. If the 
LP and cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used 
for PK and PD assessments.  A CSF sample will also be stored for testing in the event that the subject develops 
TEAEs that warrant further investigation (eg, treatment-emergent infection). (revised per Amendments 01, 02, and 
04) 
b:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization 
can be extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety 
laboratory tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
c:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
d:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
e:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At 
the Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times 
if required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
Page 482 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 85 of 144
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
f:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
g:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
h:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD19 (B cells), CD16/CD56 (natural killer cells) and CD14 (macrophages).  
Regulatory T cells will also be measured.  Viability staining may also be employed.  Whenever unscheduled 
lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a CBC with 
differentials, must also be repeated.  (revised per Amendments 02 and 04)
i:
Igs to be analyzed include IgG, IgA and IgM.
j:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
k:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine, and free thyroxine.
l:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
m:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the 
previous 12 months and provided that the scan and result are considered acceptable by the central PET reading group.  
(revised per Amendment 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops TEAEs that warrant further 
investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject 
already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurologic examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.  The Brief Smell 
Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of the neurological
examination. (revised per Amendment 04)
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 483 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 86 of 144
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
ED
b
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion 
criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological 
assessment via photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and 
urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (lymphocyte 
subset analyses)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Blood samples (Igs)m
X
X
X
X
X
X
X
X
X
X
X
Blood samples (isolation of 
PBMCs)
X
X
X
Urine pregnancy test 
(females of CBP only)
X
n
X
X
X
X
X
X
X
X
X
Blood sample (storage for 
immune status)o
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 484 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 87 of 144
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
ED
b
W2
19c
W8
20c
UNS 
Visitd
Interim 
Safety
Visit
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and 
exploratory biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and 
PDv
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 485 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 88 of 144
Footnotes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled, W2 = new Week 2 follow-up visit, W8 = new Week 8 follow-up visit.  (revised per Amendment 04)
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up 
Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (Visit W2, 19, W8, and Visit 20, respectively).  (revised per Amendments 04 and 05)  
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 4 post-treatment Follow-Up visits; 
2, 4, 8, and 12 weeks after the last dose of study drug (Visits W2, 19, W8, and 20, respectively).  If clinically indicated, more frequent safety assessments can be made as 
UNS assessments or visits during the post-treatment Follow-Up period.  (revised per Amendment 04)
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at the previous Follow-Up visit.  (revised per Amendments 02 and 
04)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive 
decline in excess of expectations based on the subject’s recent history. The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves 
as part of the neurologic examination. (revised per Amendment 04)
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [NK cells] and CD14 [macrophages]) and total lymphocytes.  Regulatory T cells will also be measured. Viability staining may also be employed.  Whenever 
unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be 
performed along with assessment of AEs. (revised per Amendments 02 and 04)
Page 486 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 89 of 144
Footnotes for Table 7
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops a TEAE that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective 
agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors.  
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images 
in MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within 
the 7 days before Visits 14, 16, 18, and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety 
MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will 
be collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14, and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  Postrandomization CSF sample collection is scheduled at Visit 7 (or later postrandomization timepoint) and Visit 
18/ED.    If a postrandomization CSF sample is collected later than Visit 7, time-matched plasma PK samples are also required (see Footnote t).  All visits at which CSF 
samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. The timing of the Baseline LP 
needs to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and 
at a similar time of day (±1 hour) for each individual subject.  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  
A gravity drip collection method must be used.  If the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  The CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already 
Page 487 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 90 of 144
Footnotes for Table 7
stopped study drug, then no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. . Subjects who initially 
consented to CSF collection and provided a baseline CSF sample but did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendments 01, 02, and 04)  
w:
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 488 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 91 of 144
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.5.2, and Figure 2.
See Section 9.5 for a full description of the procedures and assessments to be performed 
during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
20
2 x 5 mL
18 x 5 mL
100 mL
Lymphocyte subset analysesa
20
2 x 4 mL
18 x 4 mL
80 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
10
2 x 2 mL
8 x 2 mL
20 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
342 mL
422 mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 489 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 92 of 144
a:
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, 
a CBC with differentials must also be performed. Therefore, for each unscheduled or repeat test, an additional 9 mL 
will be collected (5 mL for hematology and 4 mL for lymphocyte subset analyses) 
(Table 8 revised per Amendment 04)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.5.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the final follow-up visit (Visit 20).  (revised per Amendment 
04) (revised per Amendments 04 and 05)  However, any SAEs volunteered by subjects after 
this time point must be reported according to standard procedures.  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.
Page 490 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 93 of 144
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
Page 491 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 94 of 144
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
Page 492 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 95 of 144
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study 
drug (Visits W2, 19, W8, and Visit 20, respectively) (see Section 9.1.2.3).
(revised per 
Amendment 04) See Table 7 for full details of the assessments to be performed at these 
visits.  revised per Amendment 05) Subjects who discontinue study drug early (as opposed 
to subjects whose dosing with study drug is temporarily suspended under Medical Monitor 
guidance) will not be permitted to restart study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
Page 493 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 96 of 144
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Abuse or Diversion of Study Drug eCRF. (revised per 
Amendment 04)
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Page 494 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 97 of 144
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section. Analyeses will be 
performed based on treatment group, which will be defined in the statistical analysis plan 
(SAP). Additional analyses related to dose re-assignment will be performed for subjects who 
will be switched from E2609 5 mg and 15 mg to E2609 50 mg.  Further details will be 
provided in the SAP, which will be finalized before database lock. (revised per 
Amendment 06)
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

Safety and tolerability, which include incidence of TEAEs and SAEs, laboratory 
parameters, vital signs, and ECG parameters (revised per Amendment 05)
9.7.1.1.2
SECONDARY ENDPOINTS
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after from  4 weeks and 
up to 18 months of treatment 

The population PK parameters of E2609 in CSF and plasma, including the effect of 
intrinsic and extrinsic factors (including NAT2 phenotype)
Page 495 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 98 of 144
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01, 02, 04, and 05)  
Change from baseline in:  

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) after at least 
4 weeks and at 18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment   

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and 
during posttreatment follow-up 

CSF amyloid and CSF BACE1 measurements after 4 weeks and 18 months of treatment
(revised per Amendment 06)

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months of treatment as measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain 
amyloid levels as measured

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose exploratory efficacy 
measurement.  (revised per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The number of randomized subjects enrolled at each site will be 
summarized by treatment group.  The primary reasons for screen failures (did not meet 
inclusion or met exclusion criteria, AE, lost to follow-up, withdrawal of consent, and other) 
will be presented.
Page 496 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 99 of 144
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized by treatment group using descriptive statistics.  Continuous demographic and 
baseline variables include age, MMSE and FAQ; categorical variables include sex, age group 
(≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal
AD or mild to moderate AD).  (revised per Amendment 01)  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014 or higher).  
(revised per Amendment 04) The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the Safety Analysis Set by treatment group, 
Anatomical Therapeutic Chemical class, and WHO DD preferred term.  Prior medications 
will be defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the date of the last dose.  All medications will be 
presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
Page 497 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 100 of 144
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05)
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
There is no primary efficacy endpoint.  (revised per Amendment 05)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 
18 months.  Data from early discontinuations will also be included. 
(revised per 
Amendment 05)
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01, 02, 04, and 05)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months.  Data from early discontinuations will also be 
included. (revised per Amendment 04)

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 
18 months of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 
months of treatment, and during post-treatment follow-up 

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and 
up to 18 months of treatment (revised per Amendment 06)

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by 
vMRI

Change from baseline in left and right hippocampal, whole brain, and total ventricular
volume at 6, 12 and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid 
levels
Page 498 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 101 of 144
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for E2609 concentration listings and for summaries of 
E2609 concentrations in plasma and CSF by dose and day.  E2609 metabolite PK data may 
also be listed and summarized. (revised per Amendment 04)
A population PK approach will be used to characterize the plasma PK of E2609.  For this 
approach, plasma PK data from this study will be pooled with relevant data from Phase 1 
studies.  As appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The 
PK model will be parameterized for oral clearance (CL/F) and apparent volume of 
distribution (Vz/F) for E2609. Derived exposure parameters such as steady state area under 
the concentration time curve (AUC) and average concentration (Cavg) of E2609 and other 
derived parameters will be calculated from the model using the individual estimates 
parameterized for oral clearance and dosing history.  (revised per Amendment 04)
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  The percentage change from baseline in CSF 
Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months of treatment will be analyzed and presented 
graphically. (revised per Amendment 05)  Baseline levels and changes in t-tau and p-tau will 
be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  (revised 
per Amendment 04)  
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Page 499 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 102 of 144
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
E2609 dose, plasma, and CSF exposure will be initially explored graphically and any 
emergent relationship will be explored through population PK/PD modeling. The PK/PD
relationship between plasma PK parameters with other biomarkers may also be explored 
using similar methods.  (revised per Amendment 04)  
The relationship between plasma and CSF exposure to E2609 and the clinical efficacy scales 
(eg, MMSE, CDR) will be explored graphically.  Additionally, the relationship between 
plasma exposures of E2609 and select lymphocyte parameters will be explored graphically, 
and any emergent relationship will be explored using population-based modeling methods.  
(revised per Amendment 04)  
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, vital sign measurements, and cognitive decline assessment such as CBB will be 
summarized by treatment group using descriptive statistics.  (revised per Amendment 05)
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The cumulative number and percent of subjects will be presented by 
treatment group.  Duration of exposure will be summarized using descriptive statistics as 
continuous variable as well as categorical variable in 3-month intervals and the number and 
percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
Page 500 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 103 of 144
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  A subject data listing of all 
SAEs will be provided.
Page 501 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 104 of 144
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets measured (including but not limited to CD4 [T helper cells], CD8 
[cytotoxic T cells], CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 
[macrophages] and regulatory T cells) will be summarized in the same manner as other 
laboratory parameters.  Mean lymphocyte subsets and the mean change from baseline in 
lymphocyte subsets will also be displayed graphically over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
Page 502 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 105 of 144
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include CBB (Section 9.7.1.6).  (revised per Amendment 05)
Page 503 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 106 of 144
9.7.2
Determination of Sample Size
A total of 15 subjects per dose group is deemed sufficient to derive adequate safety and 
PK/PD data to aid in the selection of appropriate doses and the design of the Phase 3 studies 
that may be planned subsequently.  (revised per Amendment 05)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis 
and perform interim analyses of these data.  Investigators, other clinical site staff, subjects,
caregivers/informants, and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when all subjects have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)  
9.7.4
Other Statistical/Analytical Issues
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 504 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 107 of 144
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Page 505 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 108 of 144
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology.
2007;68:1588-95.
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 506 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 109 of 144
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease. 
Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association 
workgroups 
on 
diagnostic 
guidelines 
for 
Alzheimer's 
disease.
Alzheimers Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 507 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 110 of 144
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 508 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 111 of 144
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 509 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 112 of 144
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 510 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 113 of 144
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 511 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 114 of 144
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 CTA 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 CTA 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 CTA 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.
Page 512 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 115 of 144
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.
Page 513 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 116 of 144
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5 g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Female:
>3.0 – 5.032
Female:
>5.0 – 20.032
Female:
>20.032
Page 514 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 117 of 144
Grade 1
Grade 2
Grade 3
Grade 4
Male:
>44 – 3.0 x 44
Male
>3.0 – 5.044
Male:
>5.0 – 20.044
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 515 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 118 of 144
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 516 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 119 of 144
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1 through Listing 5.  Medications permitted with 
restrictions are listed in Listing 6 through Listing 8.  (revised per Amendment 04) These may 
not be all-inclusive listings.  Please contact the medical monitor(s) if the investigators have 
any questions or concerns regarding any medication not listed that your subjects may be 
taking before enrollment or start during the course of the E2609-G000-202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 517 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 120 of 144
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Biaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 518 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 121 of 144
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 519 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 122 of 144
Listing 2
Prohibited Medications Within 5 Half-lives or 60 days, Whichever is Longer, 
Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa,b and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
b:
During the treatment period of the study, short term (not more than 14 days) use of steroids up to 
the equivalent of prednisolone 40 mg OD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started. Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly. Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which required 
treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset counts 
and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
Page 520 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 123 of 144
Listing 3
Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 521 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 124 of 144
Listing 4
Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 522 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 125 of 144
Listing 5
Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last 
Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 523 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 126 of 144
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Final Follow-Up Visit 
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 524 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 127 of 144
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, 
Oramorph SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
Page 525 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 128 of 144
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
PRN = Pro re nata
Page 526 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 129 of 144
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 527 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 130 of 144
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Page 528 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 131 of 144
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 529 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 132 of 144
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 530 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 133 of 144
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 531 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 134 of 144
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 532 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 135 of 144
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Page 533 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 136 of 144
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Relaxed
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 534 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 137 of 144
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 535 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 138 of 144
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
Page 536 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 139 of 144
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or 
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)    
Page 537 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 140 of 144
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and Table
12), and a 10% cut value is applied to each of the 3 CD markers of interest the following 
age-adjusted LLN values are generated: 
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
Page 538 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 141 of 144
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 539 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 142 of 144
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 540 of 1658


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 143 of 144
PROTOCOL SIGNATURE PAGE
(revised per Amendment 05)
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neurology Business Group
Eisai Inc.
Date
 Neurology Business Group
Eisai Ltd. 
Date
Neurology Business Group Eisai Inc.
Date
Page 541 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 06)
E2609-G000-202
Eisai
FINAL (v8.0):  02 Nov 2016
Confidential
Page 144 of 144
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and 
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment 
due 
to 
Alzheimer’s 
Disease 
(Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 542 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page i of xviii
REVISION HISTORY
Revisions to Version 6.0
New version/date:  Version 7.0 / 26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Remove Stage B from protocol. In 
line with this decision, the study 
objectives and endpoints have been 
modified and subjects who 
discontinue study drug early for any 
reason will no longer be required to 
complete efficacy visits after last 
dose of study drug.
This study will no longer 
be a Proof-of-Concept 
study.  
Synopsis 
Study Protocol Title
Investigators
Sites
Study Period and Phase 
of Development
Objectives
Study Design
Early Discontinuation
Number of Subjects
Study Treatments
Efficacy Assessments
Safety Assessments
Statistical Methods
Study Endpoints
Analysis Sets
Efficacy and Biomarker 
Analyses
Analysis for the 
Primary/Secondary/Explo
ratory Endpoints
Pharmacokinetic 
Analyses
Pharmacokinetic 
/Pharmacodynamic 
Analyses
Interim Analyses
Sample Size Rationale
Section 6
Section 7
Section 8
Section 8.3
Section 9.1
Section 9.2.1
Section 9.2.3
Section 9.2.4.4
Section 9.2.5
Page 543 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page ii of xviii
Revisions to Version 6.0
New version/date:  Version 7.0 / 26 Sep 2016 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Section 9.3
Section 9.4.3
Section 9.4.4
Section 9.4.7
Section 9.2.5
Section 9.5.1.3.1
Section 9.5.1.4.2
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.4.1
Section 9.5.5
Section 9.7
Section 10
Updated Eisai contact information 
Change in personnel and 
move to Building 100
Title Page
Protocol Signature Page
Page 544 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page iii of xviii
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of investigational 
sites (from 40 to 35)
Feasibility

Synopsis -
o Study Design
o Sites
Section 6
Section 9.1
Section 9.3
Removed Exclusion Criterion No. 
44 for male subjects regarding 
restrictions on child bearing  
No longer a safety concern;
E2609 has not shown a 
deleterious effect on sperm in 
preclinical reproductive toxicity 
studies.

Synopsis:
o Exclusion Criteria
Section 9.3.2
Added option for subjects who 
provided a CSF sample prior to 
randomization but who declined the 
CSF sample collection after 4 weeks 
of dosing to provide a postdose CSF 
sample at any point in the study (ie, 
even after 4 weeks of dosing).
Reflects the added value of CSF 
data for the PK/PD secondary 
objective of this study.  In 
addition, given that PK steady 
state is achieved within the 1st 
2 weeks of initiation of dosing, 
data collected post Week 4 visit 
is still considered to be 
applicable in assessment of the 
steady state effect.

Synopsis -
o Pharmacodynamic
Assessments
Section 5.3
Section 9.1
Section 9.1.1.2
Section 9.5.1.3.3
Section 9.5.1.4
Table 6
Table 7
Table 8
Revised details of restrictions to 
anticoagulant therapy and short-
term steroid use revised/moved 
details regarding antiplatelet drugs 
to the main body of the protocol
To assist in subject recruitment 
and retention and considering 
that the strict restrictions were 
not necessary for subject safety

Synopsis -
o Concomitant 
Drug/Therapy
Section 9.4.7
Appendix 2
Removed the 33% decrease from 
baseline for CD4, CD8, and CD19 
as a trigger for more frequent 
testing of flow cytometry and 
CBCs. Additional safety 
monitoring for CD4, CD8, CD19, 
and CBCs will only be based on the 
population adjusted LLNs for 
clinically asymptomatic subjects. 
Experience to date has indicated 
significant variability within the 
normal range, both for increases 
and decreases. Absolute counts 
of lymphocyte subsets are more 
meaningful than percentage 
decreases for triggering more 
frequent monitoring.
Section 9.3.3
Table 1
Table 2
Page 545 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page iv of xviii
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Added option to temporarily 
suspend study drug for subjects who 
are clinically asymptomatic but who 
meet CD4, CD8, or CD19 
discontinuation thresholds on 
2 consecutive tests.  Introduce rules 
for ability to re-start study drug (ie, 
rechallenge) in these subjects.   
Only 1 cycle of temporary 
suspension and rechallenge with 
study drug permitted for any 
individual subject.  
To assist in subject retention and 
to gain knowledge on the 
behavior of lymphocyte subsets 
on rechallenge.
Section 9.3.3
Table 1
Table 2
Added extra blood draw times with 
focus on lymphocyte subsets, 
CBCs, and immunoglobulins during 
the 12-week safety follow-up for all 
subjects.
To increase frequency of key 
safety monitoring parameters in 
post-treatment follow-up period 
so as to assess immunological 
changes after completion of 
study drug

Synopsis
o Study Design
o Safety Assessments
Section 9.1.2.2
Section 9.1.2.3
Section 9.2.5
Section 9.3.3
Table 7
Table 8
Section 9.5.1.5.7
Section 9.5.5
Clarified that the Functional 
Assessment Questionnaire is to be 
administered to the 
informant/caregiver, and not the 
subject.
Clarification

Synopsis
o Efficacy 
Assessments
Section 9.5.1.3.1
Added clarification that the Brief 
Smell Identification Test will be 
administered as part of the 
neurological examination
Clarification

Synopsis
o Safety Assessments
o Interim Analyses
Section 9.1.1.2
Section 9.5.1.2.1
Section 9.5.1.5.9
Table 6
Table 7
Page 546 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page v of xviii
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of randomized 
subjects in Stage A to n=60±20%
To allow for additional 
randomization based upon 
current number of subjects in 
screening at the time of 
amendment implementation

Synopsis
o Study Design
o No. of Subjects
Section 7
Section 9.1
Section 9.2.1
Section 9.2.5
Section 9.3
Section 9.7.3
Grammatical, typographical, and 
formatting corrections
Consistency
various
Page 547 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page vi of xviii
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder of 
the study and the full 
E2609 clinical 
development program

Synopsis –
o Exploratory Endpoint 
Analysis
o Interim Analysis
Section 9.1
Section 9.1.1.2
Section 9.4.6
Section 9.7.1.7.1
Page 548 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page vii of xviii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.5
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Appendix 2, Listing 2
Page 549 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page viii of xviii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
o
Inclusion/Exclusion
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.4.3

Section 9.3.1

Section 9.5.2

Table 6

Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/Exclusion

Section 9.3.2

Section 9.5.2

Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
Added to provide clarity 

Synopsis –
Page 550 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page ix of xviii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
for the sites.
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1

Figure 2

Section 9.5.1.3.1

Section 9.5.2

Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3

Table 1

Section 9.5.2

Table 6

Table 7
Page 551 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page x of xviii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1

Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2

Table 6
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2

Table 6

Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3

Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2

Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2

Table 6

Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 552 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xi of xviii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1

Section 9.1.1

Figure 1

Section 9.2.1

Section 9.2.2

Section 9.2.3

Section 9.2.4.3

Section 9.2.4.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.4.3

Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2

Section 9.7.1.1.3

Section 9.7.1.4

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.3

Section 9.7.4
Page 553 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xii of xviii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 

Section 5.3
Page 554 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xiii of xviii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
capacity to consent themselves.
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis –
o
Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 555 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xiv of xviii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis –
o
Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis –
o
Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis –
o
Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
o
Inclusion/Exclusion  
Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and  
International Normalized Ratio 
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
o
Inclusion/Exclusion 
Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
Page 556 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xv of xviii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –
o
Study Design  

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol.  The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20 
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis –
o
Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis –
o
Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis –
o
Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline, 
during treatment, and post-
treatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF 
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis –
o
Assessments

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6
Page 557 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xvi of xviii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis –
o
Concomitant 
Drug/Therapy

Section 7.1

Section 9.4.7

Appendix 2, Listing 6
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis –
o
Analysis of Primary 
Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis –
o
Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Page 558 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xvii of xviii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Synopsis –
o
Safety Assessments

Section 9.2.5

Section 9.5.1.5.1

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis –
o
Study Endpoints

Section 9.7.1.2
Page 559 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page xviii of xviii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.5

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 560 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 1 of 143
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-
Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects 
With Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
V6.0
29 Jun 2016 (Amendment 04)
V7.0
26 Sep 2016 (Amendment 05)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 561 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 2 of 143
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-Finding Study To Evaluate 
the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigators
Investigators in the United States only (revised per Amendment 05)
Sites
Approximately 35 sites, United States only (revised per Amendments 01, 02, 04, and 05)
Study Period and Phase of Development
Approximately 32 months (revised per Amendment 05)
Phase 2
Objectives
Primary Objective (revised per Amendment 05)

To assess the safety (including immunological and hematological parameters) and tolerability 
of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with Mild to Moderate 
Dementia due to Alzheimer's Disease (referred to as mild to moderate AD throughout the 
protocol) (revised per Amendment 01)
Secondary Objectives (revised per Amendments 02 and 05)

To characterize the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of E2609 

To assess the effects of E2609 on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and up to
18 months of treatment 
Exploratory Objectives
(revised per Amendments 01, 02, 04, and 05)

To explore the effects of E2609 on CSF Aβ(1-40) and beta (β)-amyloid converting enzyme 1 
(BACE1) measurements from 4 weeks and up to 18 months of treatment 

To explore the effects of E2609 compared with placebo on various biomarkers.  Biomarkers 
to be explored may include but are not limited to: 
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment and during post-treatment follow-up
Page 562 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 3 of 143
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale –
cognitive subscale 
(ADAS-cog14)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)
f.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)

To explore the relationship between the treatment effects of E2609 on measured clinical 
efficacy scales (eg, MMSE, CDR) and its effects on CSF amyloid, CSF amyloid isoforms, 
brain amyloid, and vMRI 

To explore relationships between both E2609 dose and exposure, with pharmacodynamic 
(PD) and safety endpoints 
Study Design
This will be a multicenter, placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common set of inclusion 
criteria, consistent with the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical 
research criteria for Mild Cognitive Impairment (MCI) due to Alzheimer’s Disease (AD) or mild to 
moderate AD, will be required for all subjects.  In addition, the MCI due to AD population will also 
be consistent with the research criterion for “Prodromal AD” in that episodic memory will be 
impaired on a list learning task (ISLT).  As the non-demented subjects will be consistent with the 
criteria for both MCI due to AD and Prodromal AD they will be identified as MCI/Prodromal 
subjects in this protocol.  The diagnosis of MCI/Prodromal AD or mild to moderate AD will be based 
on both clinical and biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists of 2 phases:  Prerandomization and Randomization.  The Prerandomization Phase 
(up to 60 days, plus an additional window of up to 30 days if required [revised per Amendment 02]) 
includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All screening assessments (within 
4 distinct tiers) must be completed, and eligibility to continue in the study confirmed, before any 
baseline assessments commence.  Following successful completion of the Prerandomization Phase, 
eligible subjects will be randomized and will enter the Randomization Phase, which will consist of 
2 periods:  Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
The study will be limited to approximately 35 sites in the United States.  (revised per Amendments 
01, 02, and 04)  Subjects will be randomized 1:1:1:1 to 4 treatment groups (5, 15, or 50 mg E2609 or 
placebo) within each of the 2 clinical populations.  (revised per Amendments 01, 04, and 05) In 
Page 563 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 4 of 143
addition to the placebo group, 3 E2609 doses will be used to reduce CSF amyloid β levels by 
approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at steady 
state.  PK/pharmacodynamic (PD) modeling has shown that these doses should achieve these targets 
when administered once daily (QD) with food, and these doses will be evaluated based on the 4-week 
(or later) assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement.  (revised per Amendment 02)
Safety data will be monitored in a blinded fashion on a regular basis.  In addition, approximately 
every 3 months from the time the 1st subject is randomized into the study, an independent data safety 
monitoring board (DSMB; including at least 1 immunologist) will review all safety data in an 
unblinded manner.  The DSMB will make recommendations to Eisai after each review as to whether 
any change(s) to the study are necessary.  (revised per Amendments 01, 04, and 05)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD profiles will 
be performed on baseline data and samples collected after at least 4 weeks of treatment.  (revised per 
Amendment 05)  These interim analyses, as well as analyses of safety data, will be performed on an 
ongoing basis throughout the study.  Refer to the Interim Analysis section for more detail. These data 
will be used to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions 
from baseline in CSF Aβ(1-x) levels.  (revised per Amendments 01 and 02)  The median and mean 
percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks or more of treatment for 
each dose of E2609 and the 90% confidence interval (CI) for the median will be derived.  In addition, 
exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the observed PK and 
PD data and will relate the average steady state plasma concentration of E2609 to CSF Aβ(1-x) 
percentage reduction from baseline determined after at least 4 weeks of dosing.  (revised per 
Amendments 01, 02, 03, 04 and 05)  
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug early) an 
interim safety analysis will be conducted by Eisai and the DSMB. Subjects will continue study drug 
while the DSMB reviews all the available safety data.  (revised per Amendments 01, 04,  and 05)
If there are safety signals with one of the E2609 dose groups that would require dose adjustment, 
changes to dose will be reflected in an amendment to the protocol.  Information on how these subjects 
will be handled in the primary analysis will be described in the Statistical Analysis Plan.
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also 
be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug. (revised per Amendments 04 and 
05)  
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study 
drug prematurely, will complete 4 post-treatment Follow-Up Visits: 2, 4, 8, and 12 weeks after the 
last dose of study drug.  If clinically indicated, more frequent safety assessments can be conducted as 
part of unscheduled visits during the post-treatment Follow-Up Period. (revised per Amendment 04)
Page 564 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 5 of 143
Number of Subjects
Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be screened to provide 
approximately 60 (±20%) randomized subjects (a target of approximately 15 subjects per treatment 
arm).  There will be no limit to the number of subjects randomized from either clinical cohort.  
(revised per Amendments 01, 02, 04, and 05)
Inclusion Criteria
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01) 
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 standard deviation (SD) from age adjusted norms in 
delayed recall on the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from 
age-adjusted norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT 
immediate recall, or 1 of the learning and memory components of the CBB).  (revised per 
Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
Page 565 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 6 of 143
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Exclusion Criteria (revised per Amendment 04)
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and <1 cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures  (revised per Amendments 01 
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for the 
testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal malformation 
on physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Page 566 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 7 of 143
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled steroids 
need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded 
(topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL 
respectively.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings.  (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
Page 567 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 8 of 143
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.  Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
Page 568 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 9 of 143
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the 1st dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study treatment period and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study treatment period or for 28 days after study 
drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the same 
contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing]).
Study Treatments
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets to match E2609 
will be of identical appearance.  Each subject will receive 2 tablets, which when combined will make 
up the required doses of E2609 or placebo, to be administered orally QD with food.  (revised per 
Amendment 05)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising:  

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, the 
duration of the pre-randomization phase can be extended by up to 4 weeks to allow additional 
time for resolution of the infection.)

Treatment Period (Randomization Phase):  up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Page 569 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 10 of 143
Concomitant Drug/Therapy
(revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit (see Appendix 2 for a detailed listing of 
these agents):  
Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 
Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days (whichever is 
longer) before randomization 
Live vaccines are not permitted within 3 months before randomization.  This does not apply to 
non-live/inactivated vaccines
Ig therapy and biologic drugs are not permitted within 6 months before randomization
Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization.  However, during 
the treatment period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started.  Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly.  Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset 
counts and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
Subjects taking AChEIs or memantine must meet the following criteria in order to be included in the 
primary analyses:  
On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2 
Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for any efficacy analyses.  
(revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  
Must be on stable dose for at least 4 weeks before randomization, except for medications that are 
administered as short courses of treatment or which are to be used intermittently as needed.  
Subjects who are on anticoagulants may have a variable dose but should have stable 
anticoagulation control for at least 4 weeks before randomization.  They may be required to stop 
their anticoagulant medication prior to CSF collection and then restart this medication after the 
LP procedure, as per local guidelines.  (revised per Amendment 04)
Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a period 
of 72 hours before cognitive testing
Page 570 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 11 of 143
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator, 
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks
Antiplatelet therapy:  (revised per Amendment 04)
For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any other 
antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and clopidogrel (or 
any other antiplatelet drug which is not aspirin) in combination are also permitted but subjects 
who are on such a combination of antiplatelet drugs may be required to stop 1 or more of these 
antiplatelet drugs before the LP procedure and restart after the LP as per local guidelines.  
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, individually 
or in combination, are permitted.   
Assessments
Efficacy Assessments
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.  
Mini-Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing.  
International Shopping List Task:  The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
CogState Brief Battery:  A computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test.  Speed of response is the measure.

Identification – a simple choice reaction time test.  Speed of response is the measure.

One Card Back – a simple working memory test.  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
Functional Assessment Questionnaire:  The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.   The caregiver or informant provides performance ratings on 
10 complex activities of daily living performed within the preceding 4 weeks.  (revised per 
Amendment 04)  
Volumetric Magnetic Resonance Imaging:  vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood samples will be collected for the determination of the concentrations of E2609.  For subjects 
who consent to CSF sample collection, CSF samples will be collected for the determination of E2609 
concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations may be 
performed depending on emerging data from other studies with E2609.
Page 571 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 12 of 143
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Brain atrophy will be measured by vMRI:  see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), (Aβ(1-40), total tau (t-tau), and p-tau will be measured in 
subjects who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and 
activity in CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) may also be 
evaluated in plasma or CSF. (revised per Amendment 04)  Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will 
be approached to consider reconsenting to postrandomization CSF sample collection even if they are 
beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
(revised per Amendment 04)
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group.  (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses. (revised per Amendments 02 and 05)
Apolipoprotein E (ApoE) and N-acetyltransferase 2 (NAT2) genotyping/phenotyping will be 
conducted.  ApoE4 homozygous or heterozygous status versus non-carriers and NAT2 status will be 
used in the statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA sequence 
variability on the absorption, distribution, metabolism, and elimination of E2609, development of 
adverse events (AEs), as well as the underlying AD.  Variations in E2609 exposure or the occurrence 
of AEs observed in the study population may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and serious adverse events (SAEs), monitoring of hematology, blood chemistry, 
and urinalysis, measurement of vital signs, regular ECGs, physical and neurological examinations, 
and centralized dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a more detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the 
frequency and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the 1st month, every 2 weeks for the next 2 months 
(Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be 
monitored every 3 months until the end of the Treatment Period and at all 4 Follow-Up Visits at 2, 4, 
8, and 12 weeks after the last dose of study drug.  Serum IgG, IgA, and IgM will be monitored 
monthly for the 1st 3 months, at 6, 12, and 18 months, and at the Follow-Up Visits that occur 4, 8, 
and 12 weeks after the last dose of study drug.  (revised per Amendment 04)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
Page 572 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 13 of 143
post-treatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments 
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects from whom CSF samples were collected (revised per 
Amendments 02 and 04).  These samples may be tested for exploratory biomarkers associated with 
study drug or disease, or in the event that a subject develops AEs that warrant further investigation 
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected infective 
agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurologic examinations will be performed at Baseline, at 6, 12, and 18 months, and at the 4- and 
12-week Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  The neurologic examinations will include 
muscle strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Small Identification Test, as well as other parts of the CNS. (revised per Amendment 04)
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and postscreening analysis of CSF Aβ(1-42), Aβ(1-40), 
t-tau, and p-tau will be performed using commercially available ELISAs.  (revised per 
Amendment 04)
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Page 573 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 14 of 143
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
Study Endpoints
Primary Endpoint

Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) 
and SAEs, laboratory parameters, vital signs, and ECG parameters (revised per Amendment 05) 
Secondary Endpoints 
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after at least 4 weeks and 
18 months of treatment

The population PK parameters of E2609 in CSF and plasma, including the effect of intrinsic and 
extrinsic factors (including NAT2 phenotype)  
Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
Change from baseline in:

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment 

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and during 
posttreatment follow-up

CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 18 months of treatment, 
and during posttreatment follow-up 

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and 18 months as 
measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain amyloid 
levels

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months:  
ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
Page 574 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 15 of 143
Analysis Sets 

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postdose exploratory efficacy measurement.  (revised 
per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at least 
1 post-treatment PD measurement.
Efficacy and Biomarker Analyses (revised per Amendment 05)
Analysis for the Primary Endpoint 
There is no primary efficacy endpoint.  (revised per Amendment 05)
Analysis for the Secondary Endpoints
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 18 months.  
Data from early discontinuations will also be included. (revised per Amendment 05)
Analysis for Exploratory Endpoints
(revised per Amendments 01, 02, 04, and 05)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) 
from 4 weeks and up to 18 months of treatment

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months 
of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 months of 
treatment, and during post-treatment follow-up

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment, and during posttreatment follow-up

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by vMRI 

Change from baseline in left and right hippocampal, whole brain, and total ventricular volume at 
6, 12, and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid levels
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, CBB, and 
FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
Page 575 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 16 of 143
correlation analysis. 
Pharmacokinetic Analyses 
The PK Analysis Set will be used for E2609 concentration listings and for summaries of E2609 
concentrations in plasma and CSF by dose and day.  E2609 metabolite PK data may also be listed and 
summarized.  (revised per Amendment 05)
A population PK approach will be used to characterize the plasma PK of E2609.  For this approach, 
plasma PK data from this study will be pooled with relevant data from Phase 1 studies.  As 
appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The PK model will be 
parameterized for oral clearance (CL/F) and apparent volume of distribution (Vz/F) for E2609. 
Derived exposure parameters such as steady state area under the concentration time curve (AUC) and 
average concentration (Cavg) of E2609 and other derived parameters will be calculated from the 
model using the individual estimates parameterized for oral clearance and dosing history. (revised 
per Amendment 04)
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma 
biomarkers, MRI endpoints).  The percentage change from baseline in CSF Aβ(1-x), Aβ(1-40), 
Aβ(1-42), t-tau, p-tau, and BACE1 variables (eg, activity and protein levels) from 4 weeks and up to 
18 months will be analyzed and presented graphically.  (revised per Amendments 04 and 05)  
Baseline levels and changes in t-tau and p-tau will be correlated with changes in CSF Aβ(1-42), 
imaging markers, and ApoE4 status.  Summary statistics for CSF biomarkers will be assessed for 
evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI and E2609 
dose, plasma and CSF exposure will be initially explored graphically and any emergent relationship 
will be explored through population PK/PD modeling.  Additionally, the relationship between CSF 
exposure to E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  (revised per Amendments 04 and 05)
Additionally, the relationship between plasma exposures of E2609 and select lymphocyte parameters 
will be explored graphically, and any emergent relationship will be explored using population-based 
modeling methods. (revised per Amendment 04)
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, vital sign measurements, and cognitive decline 
assessment such as CBB will be summarized by treatment group using descriptive statistics.  (revised 
Page 576 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 17 of 143
per Amendment 05)
Lymphocyte Subsets
Lymphocyte subsets, including but not limited to, CD4 [T helper cells], CD8 [cytotoxic T cells], 
CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells 
will be summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets 
and the mean change from baseline in lymphocyte subsets will also be displayed graphically over 
time by dose.  
Serum IgG, IgM, IgA will be measured and summarized in the same manner as other laboratory 
parameters. (revised per Amendment 04)
Interim Analyses
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and 
perform interim analyses of these data.  Investigators, other clinical site staff, subjects,  
caregivers/informants and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when 60 subjects (±20%) have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)
Stratification
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no).  (revised per Amendment 01)
Sample Size Rationale
A total of 15 subjects per dose is deemed sufficient to derive adequate safety and PK/PD data to aid 
in the selection of appropriate doses and the design of the Phase 3 studies that may be planned 
subsequently.  (revised per Amendment 04)
Page 577 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 18 of 143
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................23
5
ETHICS............................................................................................................................26
5.1
Institutional Review Boards/Independent Ethics Committees ..............................26
5.2
Ethical Conduct of the Study.................................................................................26
5.3
Subject Information and Informed Consent...........................................................27
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................29
7
INTRODUCTION ...........................................................................................................30
7.1
Nonclinical and Clinical Safety Data.....................................................................31
8
STUDY OBJECTIVES....................................................................................................34
8.1
Primary Objective..................................................................................................34
8.2
Secondary Objectives.............................................................................................34
8.3
Exploratory Objectives ..........................................................................................34
9
INVESTIGATIONAL PLAN..........................................................................................36
9.1
Overall Study Design and Plan..............................................................................36
9.1.1
Prerandomization Phase...............................................................................38
9.1.1.1
Screening Period..................................................................................39
9.1.1.2
Baseline Period ....................................................................................41
9.1.2
Randomization Phase...................................................................................41
9.1.2.1
Treatment Period..................................................................................42
9.1.2.2
Early Discontinuation ..........................................................................42
9.1.2.3
Follow-Up Period.................................................................................42
9.2
Discussion of Study Design, Including Choice of Control Groups.......................42
9.2.1
Overview......................................................................................................42
9.2.2
Rationale for Study Population....................................................................43
9.2.3
Rationale for Clinical Endpoints..................................................................44
9.2.4
Rationale for Biomarkers.............................................................................45
9.2.4.1
Overall Rationale .................................................................................45
9.2.4.2
Soluble Biomarkers in CSF .................................................................45
9.2.4.3
Amyloid PET .......................................................................................46
9.2.4.4
vMRI....................................................................................................46
9.2.5
Clinical Risks and Mitigation Strategy........................................................48
9.3
Selection of Study Population................................................................................49
Page 578 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 19 of 143
9.3.1
Inclusion Criteria .........................................................................................49
9.3.2
Exclusion Criteria ........................................................................................51
9.3.3
Removal of Subjects from Therapy or Assessment.....................................55
9.4
Treatments..............................................................................................................58
9.4.1
Treatments Administered.............................................................................58
9.4.2
Identity of Investigational Product...............................................................59
9.4.2.1
Chemical Name and Formula of E2609...............................................59
9.4.2.2
Comparator Drug .................................................................................59
9.4.2.3
Labeling for Study Drug......................................................................59
9.4.2.4
Storage Conditions...............................................................................60
9.4.3
Method of Assigning Subjects to Treatment Groups...................................60
9.4.4
Selection of Doses in the Study...................................................................60
9.4.5
Selection and Timing of Dose for Each Subject..........................................62
9.4.6
Blinding........................................................................................................62
9.4.7
Prior and Concomitant Therapy...................................................................63
9.4.8
Treatment Compliance.................................................................................64
9.4.9
Drug Supplies and Accountability...............................................................64
9.5
Study Assessments.................................................................................................66
9.5.1
Assessments.................................................................................................66
9.5.1.1
Demography.........................................................................................66
9.5.1.2
Baseline Assessments ..........................................................................66
9.5.1.2.1
Medical History and Physical Examinations.................................66
9.5.1.2.2
Viral Testing ..................................................................................67
9.5.1.2.3
B12 Testing....................................................................................67
9.5.1.2.4
TB Exposure Testing .....................................................................67
9.5.1.2.5
Urine Drug Testing ........................................................................67
9.5.1.3
Efficacy Assessments...........................................................................67
9.5.1.3.1
Psychometric Assessments ............................................................67
9.5.1.3.2
Volumetric MRI.............................................................................69
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................69
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................69
9.5.1.4.1
Pharmacokinetic Assessments .......................................................69
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................70
9.5.1.5
Safety Assessments..............................................................................72
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..72
Page 579 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 20 of 143
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................75
9.5.1.5.3
Laboratory Measurements .............................................................76
9.5.1.5.4
Vital Signs and Weight Measurements..........................................78
9.5.1.5.5
Physical Examinations...................................................................78
9.5.1.5.6
Electrocardiograms ........................................................................78
9.5.1.5.7
Safety MRI.....................................................................................79
9.5.1.5.8
Dermatological Assessment...........................................................80
9.5.1.5.9
Neurological Examination .............................................................80
9.5.1.5.10
Pregnancy Test...............................................................................80
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................81
9.5.1.5.12
Biomarker Samples........................................................................81
9.5.1.5.13
Ophthalmic Examinations..............................................................81
9.5.2
Schedule of Procedures/Assessments ..........................................................81
9.5.2.1
Schedule of Procedures/Assessments ..................................................81
9.5.2.2
Description of Procedures/Assessments Schedule...............................90
9.5.3
Appropriateness of Measurements...............................................................91
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................91
9.5.4.1
Reporting of Serious Adverse Events..................................................91
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................92
9.5.4.3
Reporting of Events Associated with Special Situations.....................93
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................93
9.5.4.3.2
Reporting of Study-Specific Events...............................................93
9.5.4.4
Expedited Reporting ............................................................................93
9.5.4.5
Breaking the Blind...............................................................................94
9.5.4.6
Regulatory Reporting of Adverse Events ............................................94
9.5.5
Completion/Discontinuation of Subjects.....................................................94
9.5.6
Abuse or Diversion of Study Drug ..............................................................95
9.5.7
Confirmation of Medical Care by Another Physician .................................95
9.6
Data Quality Assurance .........................................................................................95
9.6.1
Data Collection ............................................................................................95
9.6.2
Clinical Data Management ..........................................................................96
9.7
Statistical Methods.................................................................................................96
9.7.1
.   (revised per Amendment 05)Statistical and Analytical Plans..................96
9.7.1.1
Study Endpoints...................................................................................96
Page 580 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 21 of 143
9.7.1.1.1
Primary Endpoint...........................................................................96
9.7.1.1.2
Secondary Endpoints .....................................................................96
9.7.1.1.3
Exploratory Endpoints ...................................................................97
9.7.1.2
Definitions of Analysis Sets.................................................................97
9.7.1.3
Subject Disposition..............................................................................97
9.7.1.4
Demographic and Other Baseline Characteristics ...............................98
9.7.1.5
Prior and Concomitant Therapy...........................................................98
9.7.1.6
Efficacy and Biomarker Analyses .......................................................99
9.7.1.6.1
Primary Efficacy Analysis.............................................................99
9.7.1.6.2
Secondary Efficacy Analyses ........................................................99
9.7.1.6.3
Exploratory Efficacy Analyses ......................................................99
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................100
9.7.1.7.1
Pharmacokinetic Analyses...........................................................100
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................100
9.7.1.8
Safety Analyses..................................................................................101
9.7.1.8.1
Extent of Exposure.......................................................................101
9.7.1.8.2
Adverse Events ............................................................................101
9.7.1.8.3
Laboratory Values........................................................................103
9.7.1.8.4
Vital Signs....................................................................................104
9.7.1.8.5
Electrocardiograms ......................................................................104
9.7.1.8.6
Other Safety Analyses..................................................................104
9.7.2
Determination of Sample Size ...................................................................105
9.7.3
Interim Analysis.........................................................................................105
9.7.4
Other Statistical/Analytical Issues .............................................................105
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................105
10
REFERENCE LIST .......................................................................................................106
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....110
11.1
Changes to the Protocol .......................................................................................110
11.2
Adherence to the Protocol....................................................................................110
11.3
Monitoring Procedures.........................................................................................110
11.4
Recording of Data................................................................................................111
11.5
Identification of Source Data...............................................................................111
11.6
Retention of Records............................................................................................112
11.7
Auditing Procedures and Inspection....................................................................112
11.8
Handling of Study Drug.......................................................................................112
11.9
Publication of Results ..........................................................................................113
Page 581 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 22 of 143
11.10 Disclosure and Confidentiality ............................................................................113
11.11 Discontinuation of Study .....................................................................................113
11.12 Subject Insurance and Indemnity.........................................................................114
12
APPENDICES ...............................................................................................................115
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................56
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................57
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................61
Table 4
Clinical Laboratory Tests...........................................................................77
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™..................................78
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................82
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................85
Table 8
Summary of Blood and CSF Sample Volumes..........................................90
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202............................................................37
Figure 2
Assessments to be Performed at Screening by Tier...................................40
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................115
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........118
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 131
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................134
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................137
Page 582 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 23 of 143
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg,
1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta (β)-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carboxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
Page 583 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 24 of 143
Abbreviation
Term
ED
early discontinuation
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
Page 584 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 25 of 143
Abbreviation
Term
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 585 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 26 of 143
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 586 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 27 of 143

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 587 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 28 of 143
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for from 4 weeks and up to 18 months 
(or at Early Discontinuation).  This consent for CSF sample collection is not required for 
study eligibility. (revised per Amendments 02 and 05)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects and will be via a 
separate, optional CSF consent form for the study.  (revised per Amendment 04)
Page 588 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 29 of 143
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 35 investigational sites in the United States.
(revised per 
Amendments 01, 02, 04, and 05)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 589 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 30 of 143
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010;
Lu, et al., 2012). Once amyloid plaques form, Aβ causes BACE1 levels to increase further, 
thus accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Rosen, et al., 1984; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study is a Phase 2 study for the E2609 program, and is designed to 
establish safety in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol) and in subjects with mild to moderate AD.  (revised per Amendment 05)  Results 
from this study will guide both the decision to move into Phase 3 development and the 
selection of the dose strengths to be taken into Phase 3.    
Page 590 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 31 of 143
In the MCI/Prodromal and mild to moderate AD population, this study will compare placebo 
and 3 oral doses of E2609 (5, 15, and 50 mg) administered once daily (QD) for 18 months.  
(revised per Amendment 05)  
This study will include interim evaluations of the pharmacokinetic (PK), pharmacodynamic 
(PD), safety, and tolerability of chronic dosing with E2609. (revised per Amendment 05)  
Furthermore, there will be close monitoring of safety by an independent data safety 
monitoring board (DSMB), including a formal safety review as soon as the randomized 
subjects (n=60, ±20%) have completed at least 12 weeks of treatment, have discontinued 
study drug or have withdrawn from the study.  (revised per Amendments 04 and 05) The 
study also includes a number of exclusion criteria, specific blinded safety monitoring 
procedures and safety criteria for discontinuation of study drug in light of the preclinical and 
clinical safety data collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the PK levels of E2609 and the PD effects on BACE
activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
Page 591 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 32 of 143
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
Page 592 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 33 of 143
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 593 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 34 of 143
8
STUDY OBJECTIVES
8.1
Primary Objective
(revised per Amendment 05)
The primary objective is:  

To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendments 02 and 05)

To characterize the plasma and CSF PK of E2609 

To assess the effects of E2609 on Aβ(1-x) and Aβ(1-42) in CSF from 4 weeks and at 
18 months of treatment 
8.3
Exploratory Objectives
(revised per Amendments 01,02, 04, and 05)  
The exploratory objectives are:  

To explore the effects of E2609 compared on CSF Aβ(1-40) and BACE1 measurements 
from 4 weeks and up to 18 months of treatment 

To explore the effects of E2609 compared with placebo on various biomarkers.  
Biomarkers to be explored may include, but not limited to:  
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau 
[p-tau]) after 18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements from 4 weeks and up to 
18 months of treatment and during post-treatment follow-up
c.
Total hippocampal atrophy at 12 and 18 months of treatment, as measured by 
volumetric magnetic resonance imaging (vMRI)
d.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment 
e.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)

To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up by assessment 
of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog14)
Page 594 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 35 of 143
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The International Shopping List Task (ISLT)
e.
The CogState Brief Battery (CBB)

The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)To explore the relationship between the treatment effects of 
E2609 on measured clinical efficacy scales (eg, MMSE, CDR) and its effects on CSF 
amyloid, CSF amyloid isoforms, brain amyloid, and vMRI 

To explore relationships between both E2609 dose and exposure, with PD and safety 
endpoints 
Page 595 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 36 of 143
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study consists
of 2 phases: 
Prerandomization and Randomization.  The 
Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
All subjects (MCI/Prodromal and mild to moderate AD) will be randomized 1:1:1:1 to 
4 treatment groups (5, 15, or 50 mg E2609 or placebo) (revised per Amendments 01 and 05)  
An overview of the study design is presented in Figure 1.
Page 596 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 37 of 143
Figure 1
Design of Study E2609-G000-202
(revised per Amendments 01, 02, and 05)
R = randomization, AD = Alzheimer’s Disease, MCI = mild cognitive impairment.
This study will be limited to approximately 35 sites in the United States, with approximately 
60 (±20%) eligible subjects randomized at Visit 3, 1:1:1:1 to 4 treatment groups within each 
clinical cohort.    In addition to the placebo group, 3 doses of E2609 will be used to reduce 
CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, 
respectively, at steady state.  PK/PD modeling shows these doses should achieve these 
targets when administered QD with food and will be evaluated based on the 4-week (or later) 
assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF 
measurement (see Section 9.4.4 ). (revised per Amendments 01, 02, 04, and 05) Safety data 
will be monitored in a blinded fashion on a regular basis.  In addition, approximately every 
3 months from the time the 1st subject is randomized into the study, an independent DSMB 
(including at least 1 immunologist) will review all safety data in an unblinded manner.  The 
DSMB will make recommendations to Eisai after each review as to whether any change(s) to 
the study are necessary.  (revised per Amendments 01, 04, and 05)  
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
treatment.  (revised per Amendment 05)  Refer Section 9.7.3 for more detail.  These data will 
be used to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions 
from baseline in CSF Aβ(1-x) levels (see Section 9.4.4). The median and mean percentage 
Page 597 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 38 of 143
change from baseline in CSF Aβ(1-x) measured after 4 weeks or more of treatment for each 
dose of E2609 and the 90% confidence interval (CI) for the median will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data and will relate the average steady state plasma concentration of 
E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline determined after at 
least 4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)
Once subjects have completed at least 12 weeks of treatment (or discontinued study drug 
early), an interim safety analysis will be conducted by Eisai and the DSMB.  (revised per 
Amendments 01, 04, and 05)  Subjects will continue study drug while the DSMB reviews all 
the available safety data.  (revised per Amendment 05)  At the time of this interim safety 
analysis, some subjects will have more than 12 weeks of safety data.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol.  Similarly, if 
the interim PK/PD analyses demonstrate that further dose adjustment is required, changes to 
dose will be reflected in an amendment to the protocol.  Information on how the data from 
these subjects will be handled in the statistical analysis will be described in the Statistical 
Analysis Plan. (revised per Amendment 04)
Interim analyses are planned and are discussed in Section
9.7.3.
(revised per 
Amendment 03)
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization, the clinician will provide a judgment on the classification of a subject as 
either MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This 
judgment may be discussed and reviewed with the Sponsor or Sponsor’s representative, as 
necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
Page 598 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 39 of 143
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Page 599 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 40 of 143
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 600 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 41 of 143
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination (including 
the Brief Smell Identification Test [Sensonics Inc.]) will be performed.  (revised per 
Amendment 04) A urine pregnancy test will be conducted for females of childbearing 
potential.  Blood will be collected from all subjects for clinical chemistry and hematology, 
lymphocyte subset analyses, Ig analyses, and PD assessments.  Blood samples will be 
collected and stored for determination of a subject’s previous exposure to infective pathogens 
in the event of AEs that warrant further investigation occurring at a later point in the study.  
Psychometric assessments will be administered to the subject in the order stated in Table 6.  
The caregiver or informant needs to be present at this visit.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, a CSF sample will be obtained at this 
visit for PK and PD assessments (see Section 9.5.1.4).  (revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the N-acetyltransferase 2 (NAT2) phenotype of subjects 
enrolled in the study (see Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
Page 601 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 42 of 143
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  (revised per Amendment 05)
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug.  (revised 
per Amendments 04 and 05)  
9.1.2.3
Follow-Up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 4 posttreatment Follow-Up Visits: 2, 4, 8, and 
12 weeks after the last dose of study drug.  If clinically indicated, more frequent safety 
assessments can be conducted as part of unscheduled visits during the post-treatment 
Follow-Up Period.  (revised per Amendment 04)
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Apr 2018.  (revised 
per Amendment 05)

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The primary objective of the study is to assess the safety and tolerability of daily dosing with 
E2609 in subjects with MCI/Prodromal AD and in subjects with mild to moderate AD. 
Immunological and hematological parameters will also be assessed.  (revised per 
Amendment 04)  
Page 602 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 43 of 143
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
Secondary endpoints include CSF PK and plasma PK parameters of E2609 based on 
population PK analysis and the percentage reduction of Aβ(1-x) and Aβ(1-42) in CSF 
relative to baseline from 4 weeks and up to 18 months of treatment.
The intrinsic and 
extrinsic factors on the PK characteristics will also be explored.
Exploratory endpoints include CSF Aβ(1-40) and BACE1 measures as well as CSF 
biomarkers of neuronal degeneration (eg, t-tau and p-tau), volumetric MRI measurements, 
plasma amyloid measurements, brain amyloid levels as measured by amyloid PET and 
clinical assessments.  (revised per Amendment 05) Exploratory endpoints including 
assessments of efficacy, safety, and other biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups (Section 9.7.4)  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
Page 603 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 44 of 143
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 
2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for Clinical Endpoints
The 14-item version of the ADAS-Cog will be used in the present study since it is considered 
more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975)
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable 
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
Page 604 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 45 of 143
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment. 
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living.  The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  Volumetric magnetic resonance imaging is discussed in 
Section 9.2.4.4.
9.2.4
Rationale for Biomarkers
9.2.4.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (t-tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.4.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
Page 605 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 46 of 143
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both t-tau and p-tau are sensitive markers of axonal and neuronal degeneration (t-tau) and 
neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel with 
disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have been 
correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful predictors 
of cognitive decline and progression to dementia due to AD.  Rebalancing dysregulated 
amyloid production early in the process may positively affect the neurodegenerative process 
and thus affect these markers and benefit the disease trajectory.  Therefore, monitoring these 
markers in conjunction with amyloid imaging may provide further supportive evidence of 
disease modifying effects.  (revised per Amendment 04)
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.4.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted on subjects with Screening PET scans performed for this study 
(ie, historical scans cannot be used for the longitudinal analyses). (Revised per Amendments
02 and 05)
9.2.4.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
regions during the early stages of disease and progresses towards the anterior regions of the 
Page 606 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 47 of 143
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF t-tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Page 607 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 48 of 143
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.5
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and percentage 
change from baseline), skin rash, reoccurrence of herpes virus infections including any 
oral herpes, genital herpes or shingles, other infections, MRI changes, ECGs, and 
pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be 
questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and post-treatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
Page 608 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 49 of 143
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood and DNA samples will be taken and stored for all subjects, 
and CSF samples will be taken and stored for all subjects who consent to CSF sample 
collection (revised per Amendment 02).  These samples may be tested in the event that a 
subject develops AEs that warrant further investigation (eg, if a subject develops a 
treatment-emergent infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Treatment Period, and at the final Follow-Up Visit.

Full neurologic examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  Details of the neurologic
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using the 
detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, Baseline,
and at regular intervals during the Treatment and Follow-Up
Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 4 off-treatment Follow-Up visits 
(2, 4, 8, and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated. (revised per Amendment 04)

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Approximately 60 (±20%) eligible MCI/Prodromal or mild to moderate AD subjects will be 
randomized at approximately 35 sites in the United States (revised per Amendments 02 and 
04).  There will be no restriction to the number of subjects from either population.  
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
Page 609 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 50 of 143
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Required at Screening Visit 1:  
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
Page 610 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 51 of 143
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
Page 611 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 52 of 143
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
Page 612 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 53 of 143
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Page 613 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 54 of 143
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.

(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).  (revised per Amendment 04)
Page 614 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 55 of 143
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (see 
Section 9.1.2.3). (revised per Amendments 04 and 05)
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test but who 
has no clinical signs or symptoms of infection, will have study drug temporarily 
suspended for at least 2 weeks but no more than 4 weeks.  During this period of study 
drug suspension, lymphocyte subset counts and complete blood count (CBC) with 
differentials will continue to be tested weekly until CD4 (T helper cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) have all returned to greater than the population-adjusted 
LLN after which time study drug can be resumed.  Testing of lymphocyte subset counts 
and CBC with differentials is required weekly for 4 weeks following resumption of study 
drug administration.  Temporary suspension and rechallenge with study drug is only 
permitted once for any given subject.  If the lymphocytes and CD counts do not return to 
greater than the population-adjusted LLN within 4 weeks from the start of temporary 
suspension the subject will need to be permanently discontinued from study drug.  
(revised per Amendment 04)
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendments 02 
and 04)  During the early stages of the treatment period, where visits are conducted 
weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already scheduled to be 
Page 615 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 56 of 143
measured on a weekly basis and so additional visits or blood draws are not required.  
(revised per Amendment 02)  For these subjects, the decision as to whether the subject 
remains on study drug or is to be discontinued from study drug will be based upon 
clinical judgment and will take into account any clinical presentation in addition to the 
lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue, 
discontinue, or temporarily 
suspend study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts below 
discontinuation threshold and no clinical signs 
or symptoms of infection
Retest within 1 week along 
with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
temporarily suspend study 
drug for between 2 and 
4 weeks.  Continue weekly 
testing of lymphocyte subsets 
and CBC with differentials.  
Rechallenge with study drug 
allowed when CD4 (T helper 
cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) 
absolute counts all greater 
than population-adjusted 
LLN.  Temporary suspension 
and rechallenge permitted 
only once for each subject.
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold
Lymphocyte subset counts 
(and CBC with differentials) 
to be performed weekly until 
lymphocyte subset counts 
return to ≥ population-
adjusted LLN 
Decision will be based upon 
lymphocyte subset counts 
and clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  
(Table revised per Amendments 02 and 04)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
Page 616 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 57 of 143
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds, subjects with infections of moderate intensity will be 
discontinued from study drug (eg, subjects whose infections are not localized, or subjects 
who are systemically unwell, or who require systemic anti-infective drug treatment).   All 
subjects with infection who are discontinued from study drug will be followed for a 
period of 12 weeks or until the infection resolves/ stabilizes or until the CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have returned to 
greater than population-adjusted LLN (whichever comes latest).
(revised per 
Amendments 02 and 04)
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts below 
discontinuation threshold
If confirmed with 
repeat testing within 
1 week, then 
temporarily suspend 
study drug as per 
instructions above.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts between 
population-adjusted LLN and 
discontinuation threshold 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts always >
population-adjusted LLN 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  
(Table revised per Amendments 02 and 04)
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
Page 617 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 58 of 143
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 2, 4, 8, and 12 weeks after the last 
dose of study drug.  They will also undertake an Unscheduled Visit (with MRI) at 
approximately 4 weeks after the visit at which such MRI features were first identified.  
An MRI will also be performed at approximately the time of the final Follow-Up Visit
(Visit 20).  Additional visits for safety may be arranged if clinically indicated in the 
opinion of the investigator, including after 12 weeks after the last dose of study drug.  At 
any time during the treatment period, subjects who have asymptomatic, treatment-
emergent microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found. They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
(revised per Amendment 04)
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered are 5, 15, and 50 mg E2609 or placebo as shown below and in 
Figure 1.  (revised per Amendments 01 and 05)  Study treatment will begin on Day 1 (at the 
study site) following Randomization and will continue for approximately 78 weeks.  Please 
refer to Table 7 and Section 9.5.1.4.1 for specific information on drug administration on days 
when PK sampling is to be performed.
Page 618 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 59 of 143
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5, 15, 50 mg, or placebo.  The tablets 
will be supplied by the Sponsor in labeled blister packs.  The product release certificates for 
E2609 and placebo will be included in the clinical study report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only
Page 619 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 60 of 143

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups are 
described in Section 9.4.1. (revised per Amendments 01 and 05)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study 
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Page 620 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 61 of 143
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma 
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1 
Activity
% Reduction 
CSF A(1-x)
5 
6.2
3.3
80.3
16.2
33
15 
18.6
10
240.9
36.6
56
50 
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = beta-amyloid converting enzyme, CSF = cerebrospinal fluid, Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from 
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1 
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients.  (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 
400 mg (17.3% decrease).  No subject had infections or drug rash while receiving E2609 
100 mg QD or at lower doses in Study 002, whereas at 200 and 400 mg QD, 4 subjects had 
symptomatic orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The 
highest dose for Study 202 of 50 mg QD (tablet administered with food) is therefore 
expected to have a similar or better safety profile compared with the 100 mg QD capsule 
(administered fasted) in Study 002.  Specific exclusion criteria, blinded and unblinded safety 
monitoring procedures, and safety criteria for discontinuation from study drug are included in 
this study in order to mitigate any immunology-related risk with E2609, particularly in light 
of the progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
Interim analyses of the E2609 plasma PK for all subjects and the E2609CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
treatment.  These interim analyses, as well as analyses of safety data, will be performed on an 
ongoing basis.  Refer Section 9.7.3 for more detail. The median and mean percentage change 
from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of E2609 
and its 90% confidence interval for the median will be derived.  In addition, exploratory 
PK/PD modeling will be conducted.  This PK/PD modeling will use the observed PK and PD 
Page 621 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 62 of 143
data and will relate the average steady state plasma concentration of E2609 to steady state 
CSF Aβ(1-x) percentage reduction from baseline after at least 4 weeks of dosing.  (revised 
per Amendments 01, 02, 03, 04, and 05)
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects, caregivers/informants, and 
all clinical site personnel involved with the conduct and interpretation of the study, including 
investigators will be blinded to the treatment codes (double-blind).  In order to make 
decisions about the remainder of the study as well as the full E2609 clinical development 
program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and perform 
interim analyses of these data.  (revised per Amendment 03)  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
The PK/PD interim analyses will take place throughout the study as per Amendment 03 and 
will be conducted by an independent PK/PD scientist at the sponsor.  Any additional changes 
to dose required for this study will be reflected in a further amendment to the protocol and 
the Statistical Analysis Plan will detail how data will be handled in the primary analysis. 
(revised per Amendments 02 and 04)
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
Page 622 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 63 of 143
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1 through Listing 5.  Medications that are permitted with 
restrictions are listed in 6 through Listing 8. (revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  (revised per 
Amendment 04)

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization.  However,
during the treatment period of the study, short term (not more than 14 days) use of 
steroids up to the equivalent of prednisolone 40 mg once daily is permitted after 
discussion with the Medical Monitor. Dosing with study drug should be suspended from 
the time steroid treatment is started. Complete blood count and lymphocyte subsets 
should be determined prior to starting steroid treatment and continue to be monitored 
weekly. Study drug may be resumed after discussion with the Medical Monitor when the 
following conditions are met: (1) treatment with steroids has been completed for at least
1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte 
subset counts and CBC with differentials is required for 4 weeks following resumption of 
study drug administration.  (revised per Amendment 04)
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Page 623 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 64 of 143
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for any 
efficacy analyses.  (revised per Amendment 05)
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed.  Subjects who are on anticoagulants may have a variable dose but should have 
stable anticoagulation control for at least 4 weeks before randomization. They may be 
required to stop their anticoagulant medication prior to CSF collection and then restart 
this medication after the LP procedure, as per local guidelines.  (revised per 
Amendment 04)

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.    (revised per Amendment 05)
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any 
other antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and
clopidogrel (or any other antiplatelet drug which is not aspirin) in combination are also 
permitted but subjects who are on such a combination of antiplatelet drugs may be 
required to stop 1 or more of these antiplatelet drugs before the LP procedure and restart
after the LP as per local guidelines.   

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, are permitted.   
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement
Page 624 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 65 of 143

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study 
drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator (or if regionally required, the head of the medical institution or the 
Page 625 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 66 of 143
designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Page 626 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 67 of 143
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination (including the Brief Smell Identification Test [Sensonics Inc.]). (revised per 
Amendment 04).  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  At the Screening Visit, the recommended order of 
assessments is: MMSE, ISLT (immediate recall), CBB, ISLT (delayed recall), CBB (repeat 
CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the 
assessments are to be conducted in the following order: MMSE, CDR, ADAS-cog14, FAQ,
ISLT (immediate recall), CBB, and ISLT (delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
Page 627 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 68 of 143
Alzheimer's Disease Assessment Scale - cognitive subscale:  Discussed in Section 9.2.3.  
(revised per Amendment 05)
Clinical Dementia Rating:  The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.Mini Mental State Examination:  A 30-point 
scale that measures orientation to time and place, registration, immediate and delayed recall, 
attention, language, and drawing.  Scores range from 0 (most impaired) to 30 (no 
impairment).
ISLT:  The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects will read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
CogState Brief Battery:  The CBB is a computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.

Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.

One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
Functional Assessment Questionnaire: The caregiver or informant provides performance 
ratings (from 0 to 3) on 10 complex activities of daily living performed within the preceding 
4 weeks.  Scores range from 0 (independent) to 30 (dependent).  (revised per Amendment 04)
Page 628 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 69 of 143
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of E2609.  For 
subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of E2609 concentrations. 
(revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with E2609.
Page 629 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 70 of 143
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A 2nd PK blood sample will be collected as close as possible in time to the 
LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the 1st report of an SAE or severe unexpected AE 
and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal (Section 9.5.1.3.3).  The timing of the Baseline LP needs 
to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization 
timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  (revised per Amendment 04)  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 levels and activity.  (revised per 
Amendment 04)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
Page 630 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 71 of 143
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses.  Aβ(1-x) in both CSF and plasma will be measured using a modified 
commercially available enzyme-linked immunosorbent assay (ELISA).  The pre- and 
postscreening analysis of CSF Aβ(1-42), Aβ(1-40), t-tau, and p-tau will be performed using 
commercially available ELISAs.  (revised per Amendment 04)  BACE1 levels will be 
measured using internally developed fluorescence resonance energy transfer and ELISA 
based assay(s).  Substrates of BACE1 inhibition may also be explored using Western blots or 
other amenable methodology if clinical observations warrant and if analytes can be reliably 
tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
For subjects who consented to CSF sample collection, CSF samples from the Baseline Visit 
will also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, 
but not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, 
or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
Page 631 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 72 of 143
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of treatment (or at ED, providing the subject has received at least 
39 weeks of study drug).  Longitudinal amyloid PET imaging will only be conducted on 
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses) (Table 6).  (revised per Amendments 02 and 05)  PET 
scanning will be performed with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and post-treatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
Page 632 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 73 of 143
whether or not considered related to the investigational product (Note:  It is not necessary 
to report every sign or symptom as a separate AE if the overall disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, discontinuation of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).    Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition eCRF.  SAEs will be collected for 3 months after the 
last dose of study drug, ie, through to the final Follow-Up visit (Visit 20).  However, any 
SAEs volunteered by subjects after this time point must be reported according to standard 
procedures.  (revised per Amendments 04 and 05)
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADAS-cog14, MMSE, ISLT and CBB (see
Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment Period, 
and if this cognitive decline is considered by the investigator to be excessive relative to the 
subject’s recent AD history, this finding should be reported as an AE.  
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  
Page 633 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 74 of 143

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following AEs will require the collection of information sufficient to provide a detailed 
description of the event, treatment and outcome to the Medical Monitor for the study: any 
treatment-emergent significant laboratory abnormality; any seizures, herpes zoster infection, 
severe infection; any moderate to severe drug rash or any rash lasting more than 72 hours 
(regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the final Follow-Up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. (revised per Amendment 04)
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Page 634 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 75 of 143
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
Page 635 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 76 of 143
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Page 636 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 77 of 143
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening and Baseline only)  (revised per Amendment 02)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte T and B cell subset analyses (see Table 5).  Regulatory T cells (revised per 
Amendment 04)
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HbsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (including but not limited to CD3, CD4, CD8, CD45, CD19, 
CD16, CD56, and CD14) and total lymphocyte counts will be measured in order to provide 
the lymphocyte subset data as shown in Table 5.  In addition, Regulatory T cells will be 
measured.  Current sponsor data supports the literature showing there is an age-related 
decline in lymphocyte subsets (see Appendix 5). These data have been used to revise the 
LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts 
to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively) (revised per 
Amendments 02 and 04).  
Page 637 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 78 of 143
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
(Table 5 revised per Amendment 04)
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
Page 638 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 79 of 143
in the supine position for at least 5 minutes.
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2 Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, and 18 and at the final Follow-Up Visit 
(Visit 20).  (revised per Amendment 04) In the event of an Unscheduled Visit, the 
investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already 
performed during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and 4 Follow-Up Visits at 2, 4, 8 and 12 weeks 
after the last dose of treatment.  (revised per Amendment 04) Subjects will also undertake an 
Page 639 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 80 of 143
Unscheduled Visit (with MRI) at approximately 30 days after the visit at which such MRI 
features were first identified.  Additional visits may be arranged if clinically indicated in the 
opinion of the investigator, and may occur later than 12 weeks after the final dose of study 
drug.
9.5.1.5.8
DERMATOLOGIC ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGIC EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve; the Brief Smell Identification Test (Sensonics 
Inc.) will be administered at the same visits to objectively test olfaction.  Treatment-emergent 
abnormal neurological findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 640 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 81 of 143
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes. The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 641 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 82 of 143
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary)a
X
X
Demographics
X (Tier 1)
Medical historyb
X (Tier 1)
Prior / concomitant medicationsc
X (Tier 1)
X
Vital signs including weightd
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTe
X (Tier 1)
X
MMSEe
X (Tier 1)
X
CDRe
X (Tier 1)
X
FAQe
X (Tier 1)
X
ADAS-cog14
e
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGf
X (Tier 2)
X
Blood and urine for clinical laboratory testsg
X (Tier 2)
X
Blood for lymphocyte subset analysesh
X (Tier 2)
X
Blood for Ig analysesi
X (Tier 2)
X
Blood for viral screenj
X (Tier 2)
Blood for thyroid function testsk
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIl
X (Tier 3)
Amyloid PET scanm
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagea
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
(Table revised per Amendments 02 and 04)
Page 642 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 83 of 143
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
Subjects who initially consented to CSF collection and provided a baseline CSF sample but did not provide a 
postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample collection 
even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
For those subjects who do consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or 
at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to 
be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each individual subject. If the 
LP and cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used 
for PK and PD assessments.  A CSF sample will also be stored for testing in the event that the subject develops 
TEAEs that warrant further investigation (eg, treatment-emergent infection). (revised per Amendments 01, 02, and 
04) 
b:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization 
can be extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety 
laboratory tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
c:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
d:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
e:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At 
the Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times 
if required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
Page 643 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 84 of 143
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
f:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
g:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
h:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD19 (B cells), CD16/CD56 (natural killer cells) and CD14 (macrophages).  
Regulatory T cells will also be measured.  Viability staining may also be employed.  Whenever unscheduled 
lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a CBC with 
differentials, must also be repeated.  (revised per Amendments 02 and 04)
i:
Igs to be analyzed include IgG, IgA and IgM.
j:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
k:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine, and free thyroxine.
l:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
m:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the 
previous 12 months and provided that the scan and result are considered acceptable by the central PET reading group.  
(revised per Amendment 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops TEAEs that warrant further 
investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject 
already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurologic examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.  The Brief Smell 
Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of the neurological
examination. (revised per Amendment 04)
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 644 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 85 of 143
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visit
d
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion 
criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological 
assessment via photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and 
urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Blood samples (lymphocyte 
subset analyses)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Blood samples (Igs)m
X
X
X
X
X
X
X
X
X
X
X
Blood samples (isolation of 
PBMCs)
X
X
X
Urine pregnancy test 
(females of CBP only)
X
n
X
X
X
X
X
X
X
X
X
Blood sample (storage for 
immune status)o
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
Page 645 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 86 of 143
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visit
d
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first 
dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed 
since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and 
exploratory biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and 
PDv
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 646 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 87 of 143
Footnotes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled, W2 = new Week 2 follow-up visit, W8 = new Week 8 follow-up visit.  (revised per Amendment 04)
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up 
Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (Visit W2, 19, W8, and Visit 20, respectively).  (revised per Amendments 04 and 05)  
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 4 post-treatment Follow-Up visits; 
2, 4, 8, and 12 weeks after the last dose of study drug (Visits W2, 19, W8, and 20, respectively).  If clinically indicated, more frequent safety assessments can be made as 
UNS assessments or visits during the post-treatment Follow-Up period.  (revised per Amendment 04)
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at the previous Follow-Up visit.  (revised per Amendments 02 and 
04)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive 
decline in excess of expectations based on the subject’s recent history. The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves 
as part of the neurologic examination. (revised per Amendment 04)
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [NK cells] and CD14 [macrophages]) and total lymphocytes.  Regulatory T cells will also be measured. Viability staining may also be employed.  Whenever 
unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be 
performed along with assessment of AEs. (revised per Amendments 02 and 04)
Page 647 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 88 of 143
Footnotes for Table 7
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops a TEAE that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective 
agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors.  
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images 
in MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within 
the 7 days before Visits 14, 16, 18, and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety 
MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will 
be collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14, and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  Postrandomization CSF sample collection is scheduled at Visit 7 (or later postrandomization timepoint) and Visit 
18/ED.    If a postrandomization CSF sample is collected later than Visit 7, time-matched plasma PK samples are also required (see Footnote t).  All visits at which CSF 
samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. The timing of the Baseline LP 
needs to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and 
at a similar time of day (±1 hour) for each individual subject.  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  
A gravity drip collection method must be used.  If the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  The CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already 
Page 648 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 89 of 143
Footnotes for Table 7
stopped study drug, then no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. . Subjects who initially 
consented to CSF collection and provided a baseline CSF sample but did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendments 01, 02, and 04)  
w:
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 649 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 90 of 143
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.5.2, and Figure 2.
See Section 9.5 for a full description of the procedures and assessments to be performed 
during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
20
2 x 5 mL
18 x 5 mL
100 mL
Lymphocyte subset analysesa
20
2 x 4 mL
18 x 4 mL
80 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
10
2 x 2 mL
8 x 2 mL
20 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
342 mL
422 mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 650 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 91 of 143
a:
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, 
a CBC with differentials must also be performed. Therefore, for each unscheduled or repeat test, an additional 9 mL 
will be collected (5 mL for hematology and 4 mL for lymphocyte subset analyses) 
(Table 8 revised per Amendment 04)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.5.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose
of study drug, ie, through to the final follow-up visit (Visit 20).  (revised per Amendment 
04) (revised per Amendments 04 and 05)  However, any SAEs volunteered by subjects after 
this time point must be reported according to standard procedures.  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.
Page 651 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 92 of 143
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
Page 652 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 93 of 143
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
Page 653 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 94 of 143
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study 
drug (Visits W2, 19, W8, and Visit 20, respectively) (see Section 9.1.2.3).
(revised per 
Amendment 04) See Table 7 for full details of the assessments to be performed at these 
visits.  revised per Amendment 05) Subjects who discontinue study drug early (as opposed 
to subjects whose dosing with study drug is temporarily suspended under Medical Monitor 
guidance) will not be permitted to restart study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
Page 654 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 95 of 143
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Abuse or Diversion of Study Drug eCRF. (revised per 
Amendment 04)
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Page 655 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 96 of 143
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance.  (revised per 
Amendment 05)
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

Safety and tolerability, which include incidence of TEAEs and SAEs, laboratory 
parameters, vital signs, and ECG parameters (revised per Amendment 05)
9.7.1.1.2
SECONDARY ENDPOINTS
(revised per Amendments 02 and 05)

% reduction of Aβ(1-x) and Aβ(1-42) in CSF relative to baseline after from  4 weeks and 
up to 18 months of treatment 

The population PK parameters of E2609 in CSF and plasma, including the effect of 
intrinsic and extrinsic factors (including NAT2 phenotype)
Page 656 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 97 of 143
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01, 02, 04, and 05)  
Change from baseline in:  

CSF Aβ(1-40) and BACE1 variables (eg, activity and protein levels) after at least 
4 weeks and at 18 months of treatment 

CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 18 months of treatment   

Plasma amyloid measurements from 4 weeks and up to 18 months of treatment, and 
during posttreatment follow-up 

CSF amyloid and CSF BACE1 measurements after 4 weeks and 18 months of treatment, 
and during posttreatment follow-up

Total hippocampal volume at 12 and 18 months of treatment as measured by vMRI

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months of treatment as measured by vMRI

Amyloid PET standardized uptake value ratio (SUVR) composite at 18 months for brain 
amyloid levels as measured

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog14, CDR, MMSE, ISLT, CBB, and FAQ
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose exploratory efficacy 
measurement.  (revised per Amendment 05)

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Page 657 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 98 of 143
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014 or higher).  
(revised per Amendment 04) The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the Safety Analysis Set by treatment group, 
Anatomical Therapeutic Chemical class, and WHO DD preferred term.  Prior medications 
will be defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the date of the last dose.  All medications will be 
presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
Page 658 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 99 of 143
9.7.1.6
Efficacy and Biomarker Analyses (revised per Amendment 05)
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
There is no primary efficacy endpoint.  (revised per Amendment 05)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
An mixed-effects model with repeated measures (MMRM) will be used to analyze the following 
secondary endpoint:

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) from 4 weeks and up to 
18 months.  Data from early discontinuations will also be included. 
(revised per 
Amendment 05)
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01, 02, 04, and 05)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in CSF Aβ(1-40) and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months.  Data from early discontinuations will also be 
included. (revised per Amendment 04)

Change from baseline in CSF biomarkers of neurodegeneration (eg, t-tau and p-tau) at 
18 months of treatment

Change from baseline in plasma amyloid measurements from 4 weeks and up to 18 
months of treatment, and during post-treatment follow-up 

Change from baseline in CSF amyloid and CSF BACE1 measurements from 4 weeks and 
up to 18 months of treatment, and during post-treatment follow-up 

Change from baseline in total hippocampal atrophy at 12 and 18 months as measured by 
vMRI

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI 

Change from baseline in Amyloid PET SUVR composite at 18 months for brain amyloid 
levels
Page 659 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 100 of 143
The following efficacy endpoints will be summarized using descriptive statistics: 

Change from baseline in the clinical assessments: ADAS-cog14, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months
The relationship between efficacy endpoints and biomarker endpoints will be explored using 
correlation analysis. 
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for E2609 concentration listings and for summaries of 
E2609 concentrations in plasma and CSF by dose and day.  E2609 metabolite PK data may 
also be listed and summarized. (revised per Amendment 04)
A population PK approach will be used to characterize the plasma PK of E2609.  For this 
approach, plasma PK data from this study will be pooled with relevant data from Phase 1 
studies.  As appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The 
PK model will be parameterized for oral clearance (CL/F) and apparent volume of 
distribution (Vz/F) for E2609. Derived exposure parameters such as steady state area under 
the concentration time curve (AUC) and average concentration (Cavg) of E2609 and other 
derived parameters will be calculated from the model using the individual estimates 
parameterized for oral clearance and dosing history.  (revised per Amendment 04)
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  The percentage change from baseline in CSF 
Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 variables (eg, activity and protein 
levels) from 4 weeks and up to 18 months of treatment will be analyzed and presented 
graphically. (revised per Amendment 05)  Baseline levels and changes in t-tau and p-tau will 
be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  (revised 
per Amendment 04)  
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Page 660 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 101 of 143
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
E2609 dose, plasma, and CSF exposure will be initially explored graphically and any 
emergent relationship will be explored through population PK/PD modeling. The PK/PD 
relationship between plasma PK parameters with other biomarkers may also be explored 
using similar methods.  (revised per Amendment 04)  
The relationship between plasma and CSF exposure to E2609 and the clinical efficacy scales 
(eg, MMSE, CDR) will be explored graphically.  Additionally, the relationship between 
plasma exposures of E2609 and select lymphocyte parameters will be explored graphically, 
and any emergent relationship will be explored using population-based modeling methods.  
(revised per Amendment 04)  
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, vital sign measurements, and cognitive decline assessment such as CBB will be 
summarized by treatment group using descriptive statistics.  (revised per Amendment 05)
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The cumulative number and percent of subjects will be presented by 
treatment group.  Duration of exposure will be summarized using descriptive statistics as 
continuous variable as well as categorical variable in 3-month intervals and the number and 
percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
Page 661 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 102 of 143
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  A subject data listing of all 
SAEs will be provided.
Page 662 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 103 of 143
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets measured (including but not limited to CD4 [T helper cells], CD8 
[cytotoxic T cells], CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 
[macrophages] and regulatory T cells) will be summarized in the same manner as other 
laboratory parameters.  Mean lymphocyte subsets and the mean change from baseline in 
lymphocyte subsets will also be displayed graphically over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
Page 663 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 104 of 143
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include CBB (Section 9.7.1.6).  (revised per Amendment 05)
Page 664 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 105 of 143
9.7.2
Determination of Sample Size
A total of 15 subjects per dose group is deemed sufficient to derive adequate safety and 
PK/PD data to aid in the selection of appropriate doses and the design of the Phase 3 studies 
that may be planned subsequently.  (revised per Amendment 05)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis 
and perform interim analyses of these data.  Investigators, other clinical site staff, subjects,
caregivers/informants, and study team will remain blinded to study treatment.  (revised per 
Amendments 03 and 05)
An interim safety analysis will also be conducted when all subjects have completed 12 weeks 
of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 04, and 05)  
9.7.4
Other Statistical/Analytical Issues
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 665 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 106 of 143
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Page 666 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 107 of 143
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology.
2007;68:1588-95.
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 667 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 108 of 143
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association 
workgroups 
on 
diagnostic 
guidelines 
for 
Alzheimer's 
disease.
Alzheimers Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 668 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 109 of 143
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 669 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 110 of 143
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 670 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 111 of 143
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 671 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 112 of 143
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 672 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 113 of 143
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 CTA 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 CTA 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 CTA 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.
Page 673 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 114 of 143
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.
Page 674 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 115 of 143
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5 g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Female:
>3.0 – 5.032
Female:
>5.0 – 20.032
Female:
>20.032
Page 675 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 116 of 143
Grade 1
Grade 2
Grade 3
Grade 4
Male:
>44 – 3.0 x 44
Male
>3.0 – 5.044
Male:
>5.0 – 20.044
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 676 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 117 of 143
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 677 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 118 of 143
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1 through Listing 5.  Medications permitted with 
restrictions are listed in Listing 6 through Listing 8.  (revised per Amendment 04) These may 
not be all-inclusive listings.  Please contact the medical monitor(s) if the investigators have 
any questions or concerns regarding any medication not listed that your subjects may be 
taking before enrollment or start during the course of the E2609-G000-202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 678 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 119 of 143
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Biaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 679 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 120 of 143
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 680 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 121 of 143
Listing 2 Prohibited Medications Within 5 Half-lives or 60 days, Whichever is Longer, 
Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa,b and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
b:
During the treatment period of the study, short term (not more than 14 days) use of steroids up to 
the equivalent of prednisolone 40 mg OD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started. Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly. Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which required 
treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset counts 
and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
Page 681 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 122 of 143
Listing 3 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 682 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 123 of 143
Listing 4 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 683 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 124 of 143
Listing 5
Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last 
Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 684 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 125 of 143
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Final Follow-Up Visit 
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 685 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 126 of 143
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, 
Oramorph SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
Page 686 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 127 of 143
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
PRN = Pro re nata
Page 687 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 128 of 143
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 688 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 129 of 143
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Page 689 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 130 of 143
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 690 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 131 of 143
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 691 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 132 of 143
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 692 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 133 of 143
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 693 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 134 of 143
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Page 694 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 135 of 143
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Relaxed
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 695 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 136 of 143
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 696 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 137 of 143
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
Page 697 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 138 of 143
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)    
Page 698 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 139 of 143
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and Table
12), and a 10% cut value is applied to each of the 3 CD markers of interest the following 
age-adjusted LLN values are generated: 
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
Page 699 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 140 of 143
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 700 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 141 of 143
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 701 of 1658


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 142 of 143
PROTOCOL SIGNATURE PAGE
(revised per Amendment 05)
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild to Moderate Dementia Due to Alzheimer’s 
Disease (revised per Amendments 01 and 05)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neurology Business Group
Eisai Inc.
Date
 Neurology Business Group
Eisai Ltd. 
Date
Neurology Business Group Eisai Inc.
Date
Page 702 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 05)
E2609-G000-202
Eisai
FINAL (v7.0):  26 Sep 2016
Confidential
Page 143 of 143
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Dose-Finding Study To Evaluate the Safety and 
Tolerability of E2609 in Subjects With Mild Cognitive 
Impairment 
due 
to 
Alzheimer’s 
Disease 
(Prodromal 
Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease (revised per Amendments 01 and 05)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 703 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page i of xvi
REVISION HISTORY
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of investigational
sites (from 40 to 35)
Feasibility

Synopsis -
o Study Design
o Sites
Section 6
Section 9.1
Section 9.3
Removed Exclusion Criterion No. 
44 for male subjects regarding 
restrictions on child bearing  
No longer a safety concern;
E2609 has not shown a 
deleterious effect on sperm in 
preclinical reproductive toxicity 
studies.

Synopsis:
o Exclusion Criteria
Section 9.3.2
Added option for subjects who 
provided a CSF sample prior to 
randomization but who declined the 
CSF sample collection after 4 weeks 
of dosing to provide a postdose CSF 
sample at any point in the study (ie, 
even after 4 weeks of dosing).
Reflects the added value of CSF 
data for the PK/PD secondary 
objective of this study.  In 
addition, given that PK steady 
state is achieved within the 1st 
2 weeks of initiation of dosing, 
data collected post Week 4 visit 
is still considered to be 
applicable in assessment of the 
steady state effect.

Synopsis -
o Pharmacodynamic
Assessments
Section 5.3
Section 9.1
Section 9.1.1.2
Section 9.5.1.3.3
Section 9.5.1.4
Table 6
Table 7
Table 8
Revised details of restrictions to 
anticoagulant therapy and short-
term steroid use revised/moved 
details regarding antiplatelet drugs 
to the main body of the protocol
To assist in subject recruitment 
and retention and considering 
that the strict restrictions were 
not necessary for subject safety

Synopsis -
o Concomitant 
Drug/Therapy
Section 9.4.7
Appendix 2
Removed the 33% decrease from 
baseline for CD4, CD8, and CD19 
as a trigger for more frequent 
testing of flow cytometry and 
CBCs. Additional safety 
monitoring for CD4, CD8, CD19, 
and CBCs will only be based on the 
population adjusted LLNs for 
clinically asymptomatic subjects. 
Experience to date has indicated 
significant variability within the 
normal range, both for increases 
and decreases. Absolute counts 
of lymphocyte subsets are more 
meaningful than percentage 
decreases for triggering more 
frequent monitoring.
Section 9.3.3
Table 1
Table 2
Page 704 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page ii of xvi
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Added option to temporarily 
suspend study drug for subjects who 
are clinically asymptomatic but who 
meet CD4, CD8, or CD19 
discontinuation thresholds on 
2 consecutive tests.  Introduce rules 
for ability to re-start study drug (ie, 
rechallenge) in these subjects.   
Only 1 cycle of temporary 
suspension and rechallenge with 
study drug permitted for any 
individual subject.  
To assist in subject retention and 
to gain knowledge on the 
behavior of lymphocyte subsets 
on rechallenge.
Section 9.3.3
Table 1
Table 2
Added extra blood draw times with 
focus on lymphocyte subsets, 
CBCs, and immunoglobulins during 
the 12-week safety follow-up for all 
subjects.
To increase frequency of key 
safety monitoring parameters in 
post-treatment follow-up period 
so as to assess immunological 
changes after completion of 
study drug

Synopsis
o Study Design
o Safety Assessments
Section 9.1.2.2
Section 9.1.2.3
Section 9.2.6
Section 9.3.3
Table 7
Table 8
Section 9.5.1.5.7
Section 9.5.5
Clarified that the Functional 
Assessment Questionnaire is to be 
administered to the 
informant/caregiver, and not the 
subject.
Clarification

Synopsis
o Efficacy 
Assessments
Section 9.5.1.3.1
Added clarification that the Brief 
Smell Brief Small Identification 
Test will be administered as part of 
the neurological examination
Clarification

Synopsis
o Safety Assessments
o Interim Analyses
Section 9.1.1.2
Section 9.5.1.2.1
Section 9.5.1.5.9
Table 6
Table 7
Page 705 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page iii of xvi
Revisions to Version 5.0
New version/date:  Version 6.0 / 29 Jun 2016 (per Amendment 04)
Change
Rationale
Affected Protocol 
Sections
Revised number of randomized 
subjects in Stage A to n=60±20%
To allow for additional 
randomization based upon 
current number of subjects in 
screening at the time of 
amendment implementation

Synopsis
o Study Design
o No. of Subjects
Section 7
Section 9.1
Section 9.2.1
Section 9.2.6
Section 9.3
Section 9.7.3
Grammatical, typographical, and 
formatting corrections
Consistency
various
Page 706 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page iv of xvi
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder of 
the study and the full 
E2609 clinical 
development program

Synopsis –
o Exploratory Endpoint 
Analysis
o Interim Analysis
Section 9.1
Section 9.1.1.2
Section 9.4.6
Section 9.7.1.7.1
Page 707 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page v of xvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.6
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Appendix 2, Listing 2
Page 708 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page vi of xvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
o
Inclusion/Exclusion
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.5.3

Section 9.3.1

Section 9.5.2

Table 6

Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/Exclusion

Section 9.3.2

Section 9.5.2

Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
Added to provide clarity 

Synopsis –
Page 709 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page vii of xvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
for the sites.
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1

Figure 2

Section 9.5.1.3.1

Section 9.5.2

Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3

Table 1

Section 9.5.2

Table 6

Table 7
Page 710 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page viii of xvi
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1

Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2

Table 6
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2

Table 6

Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3

Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2

Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2

Table 6

Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 711 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page ix of xvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1

Section 9.1.1

Figure 1

Section 9.2.1

Section 9.2.2

Section 9.2.3

Section 9.2.5.3

Section 9.2.5.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.4.3

Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2

Section 9.7.1.1.3

Section 9.7.1.4

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.3

Section 9.7.4
Page 712 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page x of xvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis –
o
Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 

Section 5.3
Page 713 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xi of xvi
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
capacity to consent themselves.
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis –
o
Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis –
o
Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 714 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xii of xvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis –
o
Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis –
o
Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis –
o
Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
o
Inclusion/Exclusion  
Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and  
International Normalized Ratio 
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
o
Inclusion/Exclusion 
Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
Page 715 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xiii of xvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –
o
Study Design  

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol.  The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20 
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis –
o
Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis –
o
Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis –
o
Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline, 
during treatment, and post-
treatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis –
o
Safety Assessments

Section 9.2.6

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF 
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis –
o
Assessments

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6
Page 716 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xiv of xvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis –
o
Concomitant 
Drug/Therapy

Section 7.1

Section 9.4.7

Appendix 2, Listing 6
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis –
o
Safety Assessments

Section 9.2.6

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis –
o
Analysis of Primary 
Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis –
o
Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Page 717 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xv of xvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Synopsis –
o
Safety Assessments

Section 9.2.6

Section 9.5.1.5.1

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis –
o
Study Endpoints

Section 9.7.1.2
Page 718 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page xvi of xvi
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014 (revised original protocol)
Change
Rationale
Affected Protocol Sections
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.6

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 719 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 1 of 160
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and 
Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to 
Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
V6.0
29 Jun 2016 (Amendment 04)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 720 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 2 of 160
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, Dose-Finding 
Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive 
Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia Due to Alzheimer’s Disease (revised per Amendment 01)
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 35 sites, United States only (revised per Amendments 01, 02, and 04)
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  Approximately 42 months from initiation of Stage B (revised per Amendment 01)
Phase 2
Objectives
Primary Objectives
1.
To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect (ED90)
for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 18 months of 
treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease (referred to as MCI/Prodromal throughout the protocol)
2.
To assess the safety (including immunological and hematological parameters) and tolerability of 
daily dosing with E2609 in MCI/Prodromal subjects and in subjects with Mild to Moderate 
Dementia due to Alzheimer's Disease (referred to as mild to moderate AD throughout the 
protocol) (revised per Amendment 01)
Secondary Objectives (revised per Amendment 02)
1.
To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects, as measured by volumetric magnetic 
resonance imaging (vMRI) 
2.
To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 18 months 
in mild to moderate AD subjects (revised per Amendment 01)  
Page 721 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 3 of 160
Exploratory Objectives
(revised per Amendments 01, 02, and 04)
1.
To explore the effect of E2609 compared with placebo on the derived ADCOMS following 
12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2.
To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3.
To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ(1-42) in CSF after at 
least 4 weeks and at 18 months of treatment in MCI/Prodromal subjects and in mild to moderate 
AD subjects
4.
To explore the effects of E2609 compared with placebo on clinical status at various time points 
during 18 months of treatment, and during post-treatment follow-up, in MCI/Prodromal and mild 
to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional Activities 
Questionnaire)
f.
The International Shopping List Task (ISLT)
5.
To explore the effects of E2609 compared with placebo on various biomarkers in MCI/Prodromal 
and mild to moderate AD subjects.  Biomarkers to be explored may include but are not limited to:
a.
CSF biomarkers of neurodegeneration (eg, total tau [t-tau], phosphorylated-tau [p-tau]) after 
18 months of treatment
b.
Plasma and CSF amyloid, and CSF βeta-amyloid converting enzyme 1 (BACE1)
measurements during 18 months of treatment and during post-treatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain volume and 
total ventricular volume at 6, 12, and 18 months of treatment and during post-treatment 
follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission tomography 
(PET)
6.
To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and mild to 
moderate AD subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7.
To explore the relationship between the treatment effects of E2609 on the ADCOMS and its 
effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and mild to 
moderate AD subjects
Page 722 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 4 of 160
Study Design
This will be a multicenter, placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common set of inclusion 
criteria, consistent with the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical 
research criteria for Mild Cognitive Impairment (MCI) due to Alzheimer’s Disease (AD) or mild to 
moderate AD, will be required for all subjects.  In addition, the MCI due to AD population will also 
be consistent with the research criterion for “Prodromal AD” in that episodic memory will be 
impaired on a list learning task (ISLT).  As the non-demented subjects will be consistent with the 
criteria for both MCI due to AD and Prodromal AD they will be identified as MCI/Prodromal 
subjects in this protocol.  The diagnosis of MCI/Prodromal AD or mild to moderate AD will be based 
on both clinical and biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  After Stage A subjects have 
completed 12 weeks of treatment (or have discontinued study drug early), there will be an interim 
evaluation of the safety and tolerability of chronic dosing with E2609  before expanding enrollment 
to include a larger number of subjects in Stage B.  (revised per Amendments 01 and 04) All 
MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective of whether 
they were recruited during Stage A or Stage B.  Bayesian response adaptive randomization will be 
used in the MCI/Prodromal cohort only during Stage B.  All mild to moderate AD subjects will be 
included in the efficacy evaluations for that cohort.  (revised per Amendment 01)
Both Stage A and Stage B will consist of 2 phases:  Prerandomization and Randomization.  The 
Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if required 
[revised per Amendment 02]) includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All 
screening assessments (within 4 distinct tiers) must be completed, and eligibility to continue in the 
study confirmed, before any baseline assessments commence.  Following successful completion of 
the Prerandomization Phase, eligible subjects will be randomized and will enter the Randomization 
Phase, which will consist of 2 periods:  Treatment (78 weeks) and Follow-Up (post last dose; 
12 weeks).
Stage A
Stage A will be limited to approximately 35 sites in the United States.  (revised per Amendments 01, 
02, and 04)  Stage A will randomize approximately 60 (±20%) eligible subjects at Visit 3, 1:1:1:1 to 
4 treatment groups within each of the 2 clinical populations.  (revised per Amendments 01 and 04) In 
addition to the placebo group, 3 E2609 doses will be used to reduce CSF amyloid β levels by 
approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at steady 
state.  PK/pharmacodynamic (PD) modeling has shown that these doses should achieve these targets 
when administered once daily (QD) with food, and these doses will be evaluated based on the 4-week 
assessment of CSF Aβ(1-x) from subjects who provide voluntary consent for CSF measurement.  
(revised per Amendment 02)
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In addition, 
approximately every 3 months from the time the first subject is randomized during Stage A, an 
independent data safety monitoring board (DSMB; including at least 1 immunologist) will review all 
safety data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
review as to whether any change(s) to the study are necessary.  Unless the DSMB recommends 
otherwise, randomization of subjects into Stage A will continue until approximately 60 (±20%) 
subjects have been randomized and dosed.  (revised per Amendments 01 and 04)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD profiles will 
Page 723 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 5 of 160
be performed on baseline data and samples collectedafter at least 4 weeks of study drug.  These 
interim analyses, as well as analyses of safety data, will be performed on an ongoing basis throughout 
Stage A.  Refer to the Interim Analysis section for more detail. These data will be used to evaluate 
the CSF PD effects of E2609 doses, where PD is measured as reductions from baseline in CSF 
Aβ(1-x) levels.  (revised per Amendments 01 and 02)  The mean percentage change from baseline in 
CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of E2609 and its 90% confidence 
interval for the median will be derived.  In addition, exploratory PK/PD modeling will be conducted.  
This PK/PD modeling will use the observed PK and PD data from Stage A and will relate the average 
steady state plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction from 
baseline after 4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)  
Once Stage A subjects have completed at least 12 weeks of treatment (or discontinued study drug 
early) an interim safety analysis will be conducted by Eisai and the DSMB. (revised per Amendments
01 and 04) Subjects in Stage A will continue study drug while the DSMB reviews all the available 
safety data, but randomization of additional subjects will not take place (ie, recruitment into Stage B 
will not commence) until the safety analysis is completed by the DSMB.  
If there are safety signals with one of the E2609 dose groups that would require dose adjustment, 
changes to dose will be reflected in an amendment to the protocol.  Information on how these subjects 
will be handled in the primary analysis will be described in the Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  (revised per 
Amendment 02)  Stage B will enroll, randomize, and dose additional eligible subjects up to a 
maximum of 500 MCI/Prodromal and up to a maximum of 200 mild to moderate AD. The final total 
number of MCI/Prodromal subjects will depend upon whether the prespecified criteria for either early 
success or futility are met. (revised per Amendment 01) Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment to the study is completed; 
following this the DSMB will meet approximately every 6 months.  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort will 
include 3 doses of E2609 (5, 15, and 50 mg QD) whereas the Mild to Moderate AD cohort will only 
include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort only during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according to a 
fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  (revised per 
Amendment 01)   The remaining subjects in the MCI/Prodromal cohort in Stage B will then be 
randomized according to response adaptive randomizations based on the ADCOMS results using the 
Bayesian interim efficacy analyses.  The mild to moderate AD subjects will be randomized according 
to a fixed schedule (1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B. (revised per 
Amendment 01)
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also 
be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug. (revised per Amendment 04)  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study site for 
each scheduled visit when clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 
16, 17, and 18) if these visits have not already been performed.  At these visits, only the clinical 
Page 724 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 6 of 160
efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  
Subjects who discontinue early from study drug are considered on study as long as they return for 
their regularly scheduled clinical efficacy visits as outlined above.
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study 
drug prematurely, will complete 4 post-treatment Follow-Up Visits: 2, 4, 8, and 12 weeks after the 
last dose of study drug.  If clinically indicated, more frequent safety assessments can be conducted as 
part of unscheduled visits during the post-treatment Follow-Up Period. (revised per Amendment 04)
Number of Subjects
Stage A:  Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be screened to
provide approximately 60 (±20%) randomized subjects (a target of approximately 15 subjects per 
treatment arm).  There will be no limit to the number of subjects randomized from either clinical 
cohort.  (revised per Amendments 01, 02, and 04)
Stage B:  Up to approximately 2100 MCI/Prodromal subjects will be screened to provide up to 
500 randomized subjects.  The final number of MCI/Prodromal subjects will depend upon whether 
the prespecified criteria for either early success or futility are met.  In addition, up to approximately 
835 subjects with mild to moderate AD will be screened to provide up to 200 randomized mild to 
moderate AD subjects.  The final number of mild to moderate AD subjects randomized in Stage B 
will depend upon the number of mild to moderate AD subjects previously randomized during Stage 
A. (revised per Amendment 01)
Inclusion Criteria
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01) 
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 standard deviation (SD) from age adjusted norms in
delayed recall on the ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from 
age-adjusted norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT 
immediate recall, or 1 of the learning and memory components of the CBB).  (revised per 
Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
Page 725 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 7 of 160
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Exclusion Criteria (revised per Amendment 04)
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and <1 cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures  (revised per Amendments 01 
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is taking 
Page 726 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 8 of 160
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for the 
testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal malformation 
on physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled steroids 
need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded 
(topical steroid treatment is permitted).
Page 727 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 9 of 160
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL 
respectively.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings.  (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.  Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
Page 728 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 10 of 160
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the 1st dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study treatment period and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study treatment period or for 28 days after study 
drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the same 
contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing]).
Page 729 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 11 of 160
Study Treatments
E2609 tablets of 5-mg, 10-mg, and 25-mg dose strengths will be supplied.  Placebo tablets to match 
E2609 will be of identical appearance.  Each subject will receive 2 tablets, which when combined 
will make up the required doses of E2609 (see below) or placebo, to be administered orally QD with 
food.  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised per Amendment 01)

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised per 
Amendment 01)

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo  (revised per 
Amendment 01)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising:  

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, the 
duration of the pre-randomization phase can be extended by up to 4 weeks to allow additional 
time for resolution of the infection.)

Treatment Period (Randomization Phase):  up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Concomitant Drug/Therapy
(revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit (see Appendix 2 for a detailed listing of 
these agents):  

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days (whichever is 
longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not apply to 
non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization.  However, during 
the treatment period of the study, short term (not more than 14 days) use of steroids up to the 
equivalent of prednisolone 40 mg QD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started.  Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly.  Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
Page 730 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 12 of 160
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset 
counts and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
Subjects taking AChEIs or memantine must meet the following criteria in order to be included in the 
primary analyses:  

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2 

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for the primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications that are 
administered as short courses of treatment or which are to be used intermittently as needed.  
Subjects who are on anticoagulants may have a variable dose but should have stable 
anticoagulation control for at least 4 weeks before randomization.  They may be required to stop 
their anticoagulant medication prior to CSF collection and then restart this medication after the 
LP procedure, as per local guidelines.  (revised per Amendment 04)

Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a period 
of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator, 
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks.
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any other 
antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and clopidogrel (or 
any other antiplatelet drug which is not aspirin) in combination are also permitted but subjects 
who are on such a combination of antiplatelet drugs may be required to stop 1 or more of these 
antiplatelet drugs before the LP procedure and restart after the LP as per local guidelines.  

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, individually 
or in combination, are permitted.   
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of selected 
items (12 total) from 3 fully validated and well established clinical tools, the ADAS-cog (4 items), 
the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should be administered in full in the 
morning, or, if not possible, consistently at the same time of day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Page 731 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 13 of 160
Mini-Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery:  A computer-based battery comprising 4 cognitive tests:  

Detection – a simple reaction time test.  Speed of response is the measure.

Identification – a simple choice reaction time test.  Speed of response is the measure.

One Card Back – a simple working memory test.  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
International Shopping List Task:  The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
Functional Assessment Questionnaire:  The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.   The caregiver or informant provides performance ratings on 
10 complex activities of daily living performed within the preceding 4 weeks.  (revised per 
Amendment 04)  
Volumetric Magnetic Resonance Imaging:  vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood samples will be collected for the determination of the concentrations of E2609.  For subjects 
who consent to CSF sample collection, CSF samples will be collected for the determination of E2609 
concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations may be 
performed depending on emerging data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Brain atrophy will be measured by vMRI:  see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), (Aβ(1-40), total tau (t-tau), and p-tau will be measured in 
subjects who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and 
activity in CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers and amyloid isoforms (eg, Aβ[1-40]) may also be 
evaluated in plasma or CSF. (revised per Amendment 04)Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will 
be approached to consider reconsenting to postrandomization CSF sample collection even if they are 
beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
(revised per Amendment 04)
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group.  (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses) and will only be conducted through to the time at which 
acceptable 18-month PET scans have been obtained for at least 25 subjects per treatment arm for each 
Page 732 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 14 of 160
amyloid PET ligand used. (revised per Amendment 02)
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4 homozygous 
or heterozygous status versus non-carriers and NAT2 status will be used in the statistical analysis to 
determine the effects on treatment response and safety.  Remaining genomic DNA may also be stored 
for up to 15 years to be used to examine the role of DNA sequence variability on the absorption, 
distribution, metabolism, and elimination of E2609, development of adverse events (AEs), as well as 
the underlying AD.  Variations in E2609 exposure or the occurrence of AEs observed in the study 
population may be evaluated by correlation of single-nucleotide polymorphisms with PK, safety, or 
PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and serious adverse events (SAEs), monitoring of hematology, blood chemistry, 
and urinalysis, measurement of vital signs, regular ECGs, physical and neurological examinations, 
and centralized dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a more detailed follow-up.  Subjects 
reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the 
frequency and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the 1st month, every 2 weeks for the next 2 months 
(Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be 
monitored every 3 months until the end of the Treatment Period and at all 4 Follow-Up Visits at 2, 4, 
8, and 12 weeks after the last dose of study drug.  Serum IgG, IgA, and IgM will be monitored 
monthly for the 1st 3 months, at 6, 12, and 18 months, and at the Follow-Up Visits that occur 4, 8, 
and 12 weeks after the last dose of study drug.  (revised per Amendment 04)
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
post-treatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments 
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects from whom CSF samples were collected (revised per 
Amendments 02 and 04).  These samples may be tested for exploratory biomarkers associated with 
study drug or disease, or in the event that a subject develops AEs that warrant further investigation 
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected infective 
agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Page 733 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 15 of 160
Full neurologic examinations will be performed at Baseline, at 6, 12, and 18 months, and at the 4- and 
12-week Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  The neurologic examinations will include 
muscle strength testing and assessment of cranial nerves including olfaction, with the use of the Brief 
Small Identification Test, as well as other parts of the CNS. (revised per Amendment 04)
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and postscreening analysis of CSF Aβ(1-42), Aβ(1-40), 
t-tau, and p-tau will be performed using commercially available ELISAs.  (revised per 
Amendment 04)
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Page 734 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 16 of 160
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the Bayesian 
methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects
Secondary Endpoints 
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment  in MCI/Prodromal subjects as 
measured by vMRI

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects  (revised per 
Amendment 01)
Exploratory Endpoints
(revised per Amendments 01,02, and 04)
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to moderate AD 
subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD subjects as 
measured by vMRI

CSF Aβ(1-x) and Aβ(1-42) after at least 4 weeks and at 18 months of treatment in 
MCI/Prodromal subjects and in mild to moderate AD subjects  

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months:  
ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and mild to moderate AD 
subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months of 
treatment, and during posttreatment follow-up in MCI/Prodromal and mild to moderate AD 
subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and, 18 months in 
MCI/Prodromal and mild to moderate AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and mild to 
moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic factors 
(including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD subjects
Page 735 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 17 of 160
Analysis Sets 

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose of 
study drug and have baseline and at least 1 postdose primary efficacy measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who sufficiently comply with 
the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at least 
1 post-treatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian adaptive 
design.  Frequent interim analyses will be performed to assess the probability of early success and 
futility and to make early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the derived 
ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria if the 
probability that the ED90 at 18 months of treatment achieves 25% improvement over placebo is at 
least 80%.  Early success is achieved before all MCI/Prodromal subjects complete 18 months of 
treatment and can only be determined after at least 200 MCI/Prodromal subjects have been
randomized.  If early success is declared before full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will receive the 
full 18 months of treatment (following confirmation from the Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if the 
probability that the ED90 is better than placebo by the clinically significant difference of 25% is 
less than 5% at 18 months of treatment.  The statistical futility boundary is binding; if the 
statistical futility boundary is crossed the study will be considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if an ED90
at 18 months treatment has at least an 80% probability of achieving 25% improvement over 
placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01): All mild to moderate AD subjects 
will be included in the efficacy evaluations of the Mild to Moderate AD cohort.   The analysis of the 
Mild to Moderate AD cohort is based on the group sequential design.  Interim analyses in the Mild to 
Moderate AD cohort will only be performed after the MCI/Prodromal cohort crosses the early 
success boundary.  The early efficacy signal based on the change from baseline of ADCOMS at 
18 months is defined as crossing the interim-analysis boundaries for overwhelming efficacy in the 
mild to moderate AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets 
alpha spending function will be used to assess overwhelming efficacy.  The corresponding OF 
Page 736 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 18 of 160
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and final 
analyses, respectively, according to 2 planned interim analyses at the 60% and 80% information 
fraction. (revised per Amendment 01)
Analysis for the primary endpoint 
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the prespecified 
censoring rule applied.  The primary endpoint is the change from baseline to 18 months in the derived 
ADCOMS.  The dose-response of the primary endpoint is modelled with a first-order normal 
dynamic linear model, where Normal and Inverse-Gamma priors are used.  The primary efficacy 
analysis will calculate the Bayesian posterior probability that the dose identified is the most likely 
ED90 dose that achieves 25% improvement over the placebo arm.  At each interim analysis and the 
final analysis, 2 Bayesian probabilities will be summarized for each active dose: the probability it is
the ED90 dose and the probability of achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, CDR, CBB, ISLT, and 
FAQ), subjects will be censored at the time of initiation of treatment with AChEIs or memantine, if 
they were not on these medications at the time of Baseline cognitive assessment (Visit 2), and will be 
censored at the time of dose adjustment of AChEIs or memantine if they were already on stable 
treatment with these medications at the time of Baseline cognitive assessment (Visit 2).  The value of 
the primary endpoint for censored subjects will be imputed using data up to the censoring time and 
Bayesian longitudinal modeling.
Sensitivity analyses of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods described above 
as well as conventional statistical methods.  The following additional Bayesian analyses will be 
conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose adjustment, 
with AChEIs or memantine using the same Bayesian analysis method as primary analysis. This 
is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses will be 
repeated after all subjects have completed 18 months of treatment or have been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with repeated 
measures (MMRM) on the change from baseline in the derived ADCOMS at 18 months.  The model 
will include treatment groups, randomization stratification variables (the presence or absence of 
ongoing treatment with AChEIs or memantine or both, and ApoE4 status), and baseline ADCOMS as 
covariates.  Other covariates such as adjusted hippocampal volume will be studied.  These analyses 
will be performed as sensitivity analyses on the FAS as well as the per protocol set, and as such, no 
multiplicity adjustments will be made to account for the interim analyses.  In case of early success, 
the conventional analyses will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint: (revised per Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI
Page 737 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 19 of 160
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 18 months in 
mild to moderate AD. If there is no treatment group-by-population interaction in the overall study, 
the MMRM analysis will include all subjects (MCI/Prodromal or mild to moderate AD) in the overall 
study.  Otherwise, the MMRM analysis will only include subjects in the Mild to Moderate AD 
cohort.  The comparison between placebo and active doses will be performed within mild to moderate 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will be used 
to control for multiplicity due to multiple comparisons.
Analysis for exploratory endpoints
(revised per Amendments 01, 02, and 04)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild to 
moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to moderate AD 
subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after at least 4 weeks and at 18 months
in MCI/Prodromal and mild to moderate AD subjects.  Data from early discontinuations will also 
be included.

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, CBB, and 
FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal and mild to 
moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 4 weeks 
and 18 months of treatment, and during post-treatment follow-up in MCI/Prodromal and mild to 
moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular volume at 
6, 12, and 18 months as measured by vMRI in MCI/Prodromal and mild to moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months in 
MCI/Prodromal and mild to moderate AD subjects 

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 18 months of 
treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between each 
treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship between the 
following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in biomarkers 
in CSF at 18 months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in imaging 
biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 and 18 months in 
MCI/Prodromal and mild to moderate AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to assess the 
Page 738 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 20 of 160
effect of ApoE status in this relationship.
A population PK approach will be used to characterize the plasma PK of E2609.  For this approach, 
plasma PK data from this study will be pooled with relevant data from Phase 1 studies.  As 
appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The PK model will be 
parameterized for oral clearance (CL/F) and apparent volume of distribution (Vz/F) for E2609. 
Derived exposure parameters such as steady state area under the concentration time curve (AUC) and 
average concentration (Cavg) of E2609 and other derived parameters will be calculated from the 
model using the individual estimates parameterized for oral clearance and dosing history. (revised 
per Amendment 04)
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma 
biomarkers, MRI endpoints).  The percentage change from baseline in CSF Aβ(1-x), Aβ(1-40), 
Aβ(1-42), t-tau, p-tau, and BACE1 variables (eg, activity and protein levels) after at least 4 weeks 
and at 18 months will be analyzed and presented graphically.  (revised per Amendment 04)  Baseline 
levels and changes in t-tau and p-tau will be correlated with changes in CSF Aβ(1-42), imaging 
markers, and ApoE4 status.  Summary statistics for CSF biomarkers will be assessed for evidence of a 
dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI and E2609 
dose, plasma and CSF exposure will be initially explored graphically and any emergent relationship 
will be explored through population PK/PD modeling.  Additionally, the relationship between CSF 
exposure to E2609 and the derived ADCOMS at 18 months, and the relationship between CSF 
exposure to E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  (revised per Amendment 04)
Additionally, the relationship between plasma exposures of E2609 and select lymphocyte parameters 
will be explored graphically, and any emergent relationship will be explored using population-based 
modeling methods. (revised per Amendment 04)
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, and vital sign measurements will be summarized 
by treatment group using descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets, including but not limited to, CD4 [T helper cells], CD8 [cytotoxic T cells], 
CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells 
Page 739 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 21 of 160
will be summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets 
and the mean change from baseline in lymphocyte subsets will also be displayed graphically over 
time by dose.  
Serum IgG, IgM, IgA will be measured and summarized in the same manner as other laboratory 
parameters. (revised per Amendment 04)
Interim Analyses
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and 
perform interim analyses of these data.  Investigators, other clinical site staff, subjects and 
caregivers/informants will remain blinded to study treatment.  (revised per Amendment 03)
An interim safety analysis will also be conducted when the Stage A subjects (n=60, ±20%) have 
completed 12 weeks of treatment (or discontinue study drug early). (revised per Amendments 01, 03, 
and 04)
The MCI/Prodromal Cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be conducted 
by an independent committee that has expertise with Bayesian adaptive design in clinical studies.  An 
unblinded external independent analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim analysis 
and response adaptive randomization process through review of efficacy data.  In addition, the 
committee will act in an independent advisory capacity to monitor the Bayesian interim analysis 
outcomes according to the early success and futility boundaries prespecified in the protocol.  The 
committee will not be charged with any subject safety issues; this will remain the responsibility of the 
DSMB.  The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  The study may be stopped for safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal subjects 
have been randomized into the study (ie, including MCI/Prodromal subjects from both Stage A and 
Stage B).  (revised per Amendment 01) Further interim efficacy analyses will be conducted after 
each additional 50 MCI/Prodromal subjects have been randomized, up to a maximum of 
500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 500 subjects 
randomized).  If the study reaches full randomization, additional interim analyses will be conducted 
every 3 months until all subjects complete 18 months of treatment.  The study will be monitored for 
futility at each interim analysis.  Starting at the 200 subjects’ interim analysis, the study will be 
monitored for success at each interim analysis.  Each interim analysis will be conducted on data for 
the derived ADCOMS.  
If the predefined early success criteria are met during the recruitment period, further recruitment and 
enrollment of MCI/Prodromal subjects into the study will stop (following confirmation from the 
Sponsor’s Senior Management) and all currently randomized subjects will complete the full 
18 months of treatment.  No further interim analyses will be conducted after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized into the 
study and the treatment of subjects already randomized into the study will stop and the study will be 
declared as “failed”.  All subjects will be monitored for safety for 3 months following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all subjects 
will complete 18 months of treatment.  Interim efficacy analyses will be conducted every 3 months 
after full randomization is reached to assess futility and early success until all subjects complete 
18 months of treatment.  After full randomization, all study subjects will stop treatment only in the 
Page 740 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 22 of 160
event of futility. 
The Mild to Moderate AD Cohort (revised per Amendment 01)
A group sequential design will be used for the Mild to Moderate AD cohort.  This design includes 
3 looks, 2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the first, 
second, and final analyses, respectively.  If the actual information fraction during the interim analyses 
is different from 60% or 80% at the interim, the efficacy boundaries will be adjusted based on the 
actual information fraction.  If early success in the MCI/Prodromal cohort is not achieved before the 
final analysis that is performed when all subjects have completed 18 months treatment, then only a 
final analysis will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort based on 
the data for mild to moderate AD subjects available at that time.  (revised per Amendment 01)
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses
for the first 100 MCI/Prodromal subjects randomized, including  those randomized from both Stage 
A and Stage B).  Thereafter, randomization probabilities to each treatment group will be updated at 
each interim analysis, such that the randomization probability will be increased for the placebo group 
and dosage groups that represent the potential target dose (ED90), and simultaneously decreased for 
other active arms.  (revised per Amendment 01)
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 dose 
groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to moderate AD 
subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 50 mg E2609) at a 
1:1:1 ratio. (revised per Amendment 01)
Stratification (revised per Amendment 01)
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no).  (revised per Amendment 01)
Page 741 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 23 of 160
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by means of 
simulations.  Extensive study simulations have shown that a total of 500 subjects will be sufficient to 
demonstrate that the most likely ED90 dose achieves a 25% improvement over placebo with a 
probability of at least 80% in the interim and final analyses.  There is at least a 90% probability of 
study success for the dose response scenarios where treatment was considered to have a clinically 
meaningful treatment effect.  Simulations have also shown that if there is no obvious dose effect, the 
probability of falsely claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects per 
group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 1 null 
hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s method with 1-sided 
alpha of 0.05.  The statistical power was estimated through simulation for a moderate dose-response 
assumption that the percent reduction in change from baseline of total hippocampal volume compared 
with placebo would be 15%, 20%, and 25% corresponding to the 3 doses, respectively.  The 
estimated power for actual planned study sample size is 78% at 18 months assuming an attrition rate 
of 20% at 18 months.  Under a stronger dose-response assumption (ie, the percent reduction in 
change from baseline of total hippocampal volume compared with placebo is twice as much as that in 
the moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those for 
vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of change from baseline was estimated at 0.33 and a reasonable mean difference between 
treatment and placebo was estimated as 0.25 (standardized uptake value ratio [SUVR]).  Assuming a 
moderate dose-response, the best dose would achieve a difference of 0.25 (SUVR) and the middle 
and low doses would achieve a difference of 0.2 and 0.15 (SUVR), respectively, it would require a 
total of 100 subjects from all 4 arms at 18 months to achieve 80% power.
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per Amendment 01)
ADCOMS at Month 18: The null hypothesis is that there is no difference between active dose and 
placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in the secondary analysis 
section.  The statistical power was estimated through simulation for the dose-response assumption 
that the percent reduction in change from baseline of ADCOMS at 18 months compared with placebo 
would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated power for the 
actual planned 200 mild to moderate AD subjects is approximately 80% assuming a 2-sided alpha of 
0.05. (revised per Amendment 01)
Page 742 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 24 of 160
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................29
5
ETHICS............................................................................................................................32
5.1
Institutional Review Boards/Independent Ethics Committees ..............................32
5.2
Ethical Conduct of the Study.................................................................................32
5.3
Subject Information and Informed Consent...........................................................33
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................35
7
INTRODUCTION ...........................................................................................................36
7.1
Nonclinical and Clinical Safety Data.....................................................................37
8
STUDY OBJECTIVES....................................................................................................40
8.1
Primary Objectives.................................................................................................40
8.2
Secondary Objectives.............................................................................................40
8.3
Exploratory Objectives ..........................................................................................40
9
INVESTIGATIONAL PLAN..........................................................................................42
9.1
Overall Study Design and Plan..............................................................................42
9.1.1
Prerandomization Phase...............................................................................45
9.1.1.1
Screening Period..................................................................................46
9.1.1.2
Baseline Period ....................................................................................48
9.1.2
Randomization Phase...................................................................................48
9.1.2.1
Treatment Period..................................................................................49
9.1.2.2
Early Discontinuation ..........................................................................49
9.1.2.3
Follow-Up Period.................................................................................49
9.2
Discussion of Study Design, Including Choice of Control Groups.......................50
9.2.1
Overview......................................................................................................50
9.2.2
Rationale for Study Population....................................................................51
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................52
9.2.4
Rationale for Clinical Endpoints..................................................................52
9.2.5
Rationale for Biomarkers.............................................................................53
9.2.5.1
Overall Rationale .................................................................................53
9.2.5.2
Soluble Biomarkers in CSF .................................................................54
9.2.5.3
Amyloid PET .......................................................................................54
9.2.5.4
vMRI....................................................................................................55
9.2.6
Clinical Risks and Mitigation Strategy........................................................56
Page 743 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 25 of 160
9.3
Selection of Study Population................................................................................57
9.3.1
Inclusion Criteria .........................................................................................58
9.3.2
Exclusion Criteria ........................................................................................59
9.3.3
Removal of Subjects from Therapy or Assessment.....................................63
9.4
Treatments..............................................................................................................67
9.4.1
Treatments Administered.............................................................................67
9.4.2
Identity of Investigational Product...............................................................68
9.4.2.1
Chemical Name and Formula of E2609...............................................68
9.4.2.2
Comparator Drug .................................................................................68
9.4.2.3
Labeling for Study Drug......................................................................68
9.4.2.4
Storage Conditions...............................................................................69
9.4.3
Method of Assigning Subjects to Treatment Groups...................................69
9.4.4
Selection of Doses in the Study...................................................................69
9.4.5
Selection and Timing of Dose for Each Subject..........................................71
9.4.6
Blinding........................................................................................................71
9.4.7
Prior and Concomitant Therapy...................................................................72
9.4.8
Treatment Compliance.................................................................................74
9.4.9
Drug Supplies and Accountability...............................................................74
9.5
Study Assessments.................................................................................................76
9.5.1
Assessments.................................................................................................76
9.5.1.1
Demography.........................................................................................76
9.5.1.2
Baseline Assessments ..........................................................................76
9.5.1.2.1
Medical History and Physical Examinations.................................76
9.5.1.2.2
Viral Testing ..................................................................................76
9.5.1.2.3
B12 Testing....................................................................................76
9.5.1.2.4
TB Exposure Testing .....................................................................77
9.5.1.2.5
Urine Drug Testing ........................................................................77
9.5.1.3
Efficacy Assessments...........................................................................77
9.5.1.3.1
Psychometric Assessments ............................................................77
9.5.1.3.2
Volumetric MRI.............................................................................79
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................79
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................79
9.5.1.4.1
Pharmacokinetic Assessments .......................................................79
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................80
9.5.1.5
Safety Assessments..............................................................................82
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..82
Page 744 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 26 of 160
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................85
9.5.1.5.3
Laboratory Measurements .............................................................86
9.5.1.5.4
Vital Signs and Weight Measurements..........................................88
9.5.1.5.5
Physical Examinations...................................................................88
9.5.1.5.6
Electrocardiograms ........................................................................88
9.5.1.5.7
Safety MRI.....................................................................................89
9.5.1.5.8
Dermatological Assessment...........................................................90
9.5.1.5.9
Neurological Examination .............................................................90
9.5.1.5.10
Pregnancy Test...............................................................................90
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................91
9.5.1.5.12
Biomarker Samples........................................................................91
9.5.1.5.13
Ophthalmic Examinations..............................................................91
9.5.2
Schedule of Procedures/Assessments ..........................................................91
9.5.2.1
Schedule of Procedures/Assessments ..................................................91
9.5.2.2
Description of Procedures/Assessments Schedule.............................100
9.5.3
Appropriateness of Measurements.............................................................101
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations............................................................101
9.5.4.1
Reporting of Serious Adverse Events................................................101
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................102
9.5.4.3
Reporting of Events Associated with Special Situations...................102
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................103
9.5.4.3.2
Reporting of Study-Specific Events.............................................103
9.5.4.4
Expedited Reporting ..........................................................................103
9.5.4.5
Breaking the Blind.............................................................................104
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................104
9.5.5
Completion/Discontinuation of Subjects...................................................104
9.5.6
Abuse or Diversion of Study Drug ............................................................105
9.5.7
Confirmation of Medical Care by Another Physician ...............................105
9.6
Data Quality Assurance .......................................................................................105
9.6.1
Data Collection ..........................................................................................105
9.6.2
Clinical Data Management ........................................................................106
9.7
Statistical Methods...............................................................................................106
9.7.1
Statistical and Analytical Plans..................................................................106
9.7.1.1
Study Endpoints.................................................................................106
Page 745 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 27 of 160
9.7.1.1.1
Primary Endpoint.........................................................................106
9.7.1.1.2
Secondary Endpoints ...................................................................107
9.7.1.1.3
Exploratory Endpoints .................................................................107
9.7.1.2
Definitions of Analysis Sets...............................................................107
9.7.1.3
Subject Disposition............................................................................108
9.7.1.4
Demographic and Other Baseline Characteristics .............................109
9.7.1.5
Prior and Concomitant Therapy.........................................................109
9.7.1.6
Efficacy Analyses ..............................................................................109
9.7.1.6.1
Primary Efficacy Analysis...........................................................110
9.7.1.6.2
Secondary Efficacy Analyses ......................................................111
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................112
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................113
9.7.1.7.1
Pharmacokinetic Analyses...........................................................113
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................113
9.7.1.8
Safety Analyses..................................................................................114
9.7.1.8.1
Extent of Exposure.......................................................................115
9.7.1.8.2
Adverse Events ............................................................................115
9.7.1.8.3
Laboratory Values........................................................................116
9.7.1.8.4
Vital Signs....................................................................................117
9.7.1.8.5
Electrocardiograms ......................................................................117
9.7.1.8.6
Other Safety Analyses..................................................................117
9.7.2
Determination of Sample Size ...................................................................118
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................118
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort 
(revised per Amendment 01) .............................................................119
9.7.3
Interim Analysis.........................................................................................119
9.7.4
Other Statistical/Analytical Issues .............................................................121
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................122
10
REFERENCE LIST .......................................................................................................123
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....127
11.1
Changes to the Protocol .......................................................................................127
11.2
Adherence to the Protocol....................................................................................127
11.3
Monitoring Procedures.........................................................................................127
11.4
Recording of Data................................................................................................128
11.5
Identification of Source Data...............................................................................128
11.6
Retention of Records............................................................................................129
Page 746 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 28 of 160
11.7
Auditing Procedures and Inspection....................................................................129
11.8
Handling of Study Drug.......................................................................................129
11.9
Publication of Results ..........................................................................................130
11.10 Disclosure and Confidentiality ............................................................................130
11.11 Discontinuation of Study .....................................................................................130
11.12 Subject Insurance and Indemnity.........................................................................131
12
APPENDICES ...............................................................................................................132
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................65
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................66
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................70
Table 4
Clinical Laboratory Tests...........................................................................87
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™..................................88
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................92
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................95
Table 8
Summary of Blood and CSF Sample Volumes........................................100
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202............................................................43
Figure 2
Assessments to be Performed at Screening by Tier...................................47
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................132
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........135
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 148
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................151
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................154
Page 747 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 29 of 160
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg,
1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carboxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
Page 748 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 30 of 160
Abbreviation
Term
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
ED90
lowest effective dose that achieves 90% of the greatest treatment effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
Page 749 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 31 of 160
Abbreviation
Term
MMRM
mixed-effects model with repeated measures
MMSE
MiniMental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OF
O’Brien-Fleming 
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 750 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 32 of 160
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 751 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 33 of 160

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 752 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 34 of 160
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for 4 weeks and 18 months (or at Early 
Discontinuation).  This consent for CSF sample collection is not required for study eligibility. 
(revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects and will be via a 
separate, optional CSF consent form for the study.   (revised per Amendment 04)
Page 753 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 35 of 160
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 35 investigational sites in the United States for Stage A and 
125 sites globally for Stage B. (revised per Amendments 01, 02, and 04)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 754 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 36 of 160
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010;
Lu, et al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, 
thus accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Rosen, et al., 1984; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild to moderate dementia due to Alzheimer’s Disease (referred to as mild to moderate AD
throughout the protocol) to determine whether the effects of E2609 in this later stage 
population are comparable with those established in the MCI/Prodromal population within 
Page 755 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 37 of 160
this same study. (revised per Amendment 01)  In the MCI/Prodromal population, Bayesian 
response adaptive randomization design is used with frequent interim analyses to continually 
update randomization allocation based on emerging clinical endpoint data.  This approach 
allows for ongoing assessment of drug futility or evidence of early success and can mitigate 
the risks associated with larger and longer studies required to demonstrate clinical efficacy 
by leading to more efficient study termination or early advancement to a Phase 3 program.  
Results from this study will guide both the decision to move into Phase 3 development and 
the selection of the dose strengths to be taken into Phase 3.  Moreover, this study is intended 
to be supportive for registration in the MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5, 15, and 50 mg) administered once daily (QD) for 18 months.  In the mild to moderate AD 
population, this study will compare placebo and 2 oral doses of E2609 (15 and 50 mg) 
administered QD for 18 months.  To date, the longest duration of dosing with E2609 is 
14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  (revised per 
Amendment 01)  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the Stage A subjects (n=60, ±20%) have completed 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  (revised per Amendment 04) 
The study also includes a number of exclusion criteria, specific blinded safety monitoring 
procedures and safety criteria for discontinuation of study drug in light of the preclinical and 
clinical safety data collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
Page 756 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 38 of 160
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the PK levels of E2609 and the PD effects on BACE
activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
Page 757 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 39 of 160
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 758 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 40 of 160
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendment 02)
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild to moderate AD subjects (revised per Amendment 01)  
8.3
Exploratory Objectives
(revised per Amendments 01,02, and 04)  
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after at least 4 weeks and at 18 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects
4. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during post-treatment follow-up, in 
MCI/Prodromal and mild to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
Page 759 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 41 of 160
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
5. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild to moderate AD subjects.  Biomarkers to be explored include, 
but not limited to:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during post-treatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
post-treatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
6. To characterize the population PK of E2609 in MCI/Prodromal and mild to moderate AD 
subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild to moderate AD subjects
Page 760 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 42 of 160
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) before expanding enrollment to include a larger number of subjects in Stage B.  
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective 
of whether they were recruited into Stage A or Stage B.  Bayesian response adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B.  All mild to 
moderate AD subjects will be included in the efficacy evaluation of that cohort. (revised per 
Amendment 01)  
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
In Stage A, all subjects (MCI/Prodromal and mild to moderate AD) will be randomized 
1:1:1:1 to 4 treatment groups (E2609 at 3 doses or placebo).  In Stage B, randomization of 
MCI/Prodromal subjects will start off at a 1:1:1:1 ratio (E2609 at 3 doses or placebo), until a 
total of 100 MCI/Prodromal subjects have been randomized.  Remaining subjects in the 
MCI/Prodromal cohort will be randomized according to response adaptive randomizations 
based on the ADCOMS results using the Bayesian interim efficacy analyses.  Subjects with 
mild to moderate AD who are recruited in Stage B will be randomized in a 1:1:1 ratio to 
3 treatment groups (E2609 at 2 doses or placebo). (revised per Amendment 01)  
Page 761 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 43 of 160
An overview of the study design is presented in Figure 1.
Figure 1
Design of Study E2609-G000-202
(revised per Amendments 01 and 02)
R = randomization, AD = Alzheimer’s Disease, MCI = mild cognitive impairment.
Page 762 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 44 of 160
Stage A
Stage A will be limited to approximately 35 sites in the United States.  Stage A will 
randomize approximately 60 (±20%) eligible subjects at Visit 3, 1:1:1:1 to 4 treatment 
groups within each clinical cohort.    There will be no Bayesian adaptation during Stage A.  
In addition to the placebo group, 3 doses of E2609 will be used to reduce CSF Aβ levels by 
approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at 
steady state.  PK/PD modeling shows these doses should achieve these targets when 
administered QD with food and will be evaluated based on the 4-week assessment of CSF 
Aβ(1-x) from subjects who provide voluntary consent for CSF measurement (see 
Section 9.4.4 ). (revised per Amendments 01, 02, and 04)During Stage A, safety data will be 
monitored in a blinded fashion on a regular basis.  In addition, approximately every 3 months 
from the time the 1st subject is randomized during Stage A, an independent DSMB 
(including at least 1 immunologist) will review all safety data in an unblinded manner.  The 
DSMB will make recommendations to Eisai after each review as to whether any change(s) to 
the study are necessary.  Unless the DSMB recommends otherwise, randomization of 
subjects into Stage A will continue until approximately 60 subjects (±20%) have been 
randomized and dosed.  (revised per Amendments 01 and 04)  
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
Interim analyses of the E2609 plasma PK for all subjects and the E2609 CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
study drug.  These interim analyses, as well as analyses of safety data, will be performed on 
an ongoing basis throughout Stage A.  Refer Section 9.7.3 for more detail.  These data will 
be used to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions 
from baseline in CSF Aβ(1-x) levels (see Section 9.4.4). The median and mean percentage 
change from baseline in CSF Aβ(1-x) measured after 4 weeks or more of treatment for each 
dose of E2609 and the 90% confidence interval (CI) for the median will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data and will relate the average steady state plasma concentration of 
E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline determined after at 
least 4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)
Once Stage A subjects have completed at least 12 weeks of treatment (or discontinued study 
drug early) an interim safety analysis will be conducted by Eisai and the DSMB.  (revised per 
Amendments 01 and 04)  Subjects in Stage A will continue study drug while the DSMB 
reviews all the available safety data, but randomization of additional subjects will not take 
place (ie, recruitment into Stage B will not commence) until the safety analysis is completed 
by the DSMB.  At the time of this interim safety analysis, some subjects will have more than 
12 weeks of safety data.  
Page 763 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 45 of 160
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol.  Similarly, if 
the interim PK/PD analyses demonstrate that further dose adjustment is required, changes to 
dose will be reflected in an amendment to the protocol.  Information on how the data from 
these subjects will be handled in the statistical analysis will be described in the Statistical 
Analysis Plan. (revised per Amendment 04)
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  
(revised per Amendment 02) Based on data from Stage A, the protocol will be reviewed and 
may be amended before beginning Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment in the study is 
completed; following this the DSMB will meet approximately every 6 months.
Stage B will be conducted globally and will enroll, randomize, and dose additional eligible 
subjects up to a maximum of 500 MCI/Prodromal subjects and up to a maximum of 200 mild 
to moderate AD subjects. The final total number of MCI/Prodromal subjects will depend 
upon whether the prespecified criteria for either early success or futility are met.  (revised per 
Amendment 01)  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5, 15, and 50 mg QD), whereas the Mild to Moderate AD 
cohort will only include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)  
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according 
to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  
(revised per Amendment 01)  The remaining subjects in the MCI/Prodromal cohort in Stage 
B will then be randomized according to response adaptive randomizations based on the 
ADCOMS results using the Bayesian interim efficacy analyses.  The mild to moderate AD 
subjects will be randomized according to a fixed schedule (1:1:1 placebo; 15 mg E2609; 
50 mg E2609) throughout Stage B. (revised per Amendment 01)  
Interim analyses are planned and are discussed in Section 9.7.3. (revised per 
Amendment 03)
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
Page 764 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 46 of 160
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization, the clinician will provide a judgment on the classification of a subject as 
either MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This 
judgment may be discussed and reviewed with the Sponsor or Sponsor’s representative, as 
necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Page 765 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 47 of 160
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 766 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 48 of 160
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination (including 
the Brief Smell Identification Test [Sensonics Inc.]) will be performed.  (revised per 
Amendment 04) A urine pregnancy test will be conducted for females of childbearing 
potential.  Blood will be collected from all subjects for clinical chemistry and hematology, 
lymphocyte subset analyses, Ig analyses, and PD assessments.  Blood samples will be 
collected and stored for determination of a subject’s previous exposure to infective pathogens 
in the event of AEs that warrant further investigation occurring at a later point in the study.  
Psychometric assessments will be administered to the subject in the order stated in Table 6.  
The caregiver or informant needs to be present at this visit.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, a CSF sample will be obtained at this 
visit for PK and PD assessments (see Section 9.5.1.4).  (revised per Amendment 02)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
Page 767 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 49 of 160
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug.  (revised 
per Amendment 04)Subjects who discontinue study drug prematurely will also be scheduled 
to return to the study site for each scheduled visit when clinical efficacy assessments are to 
be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been 
performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, 
FAQ, CBB and ISLT) will be conducted.  Regularly scheduled clinical efficacy visits do not 
need to be attended if they fall within 8 days (visit window) after the Early Discontinuation 
Visit or within ±8 days of Follow-Up Visit 19 or Visit 20.  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. (revised per Amendment 04)
9.1.2.3
Follow-Up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 4 post-treatment Follow-Up Visits: 2, 4, 8, and 
12 weeks after the last dose of study drug.  If clinically indicated, more frequent safety 
assessments can be conducted as part of unscheduled visits during the post-treatment Follow-
Up Period.  (revised per Amendment 04)
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Oct 2019 (end date 
will depend on actual recruitment rate).

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
Page 768 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 50 of 160
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The 2 stage design of the study allows for the safety and tolerability of E2609 to be assessed 
in a limited number of subjects (n=60±20%) before expanding recruitment into a larger 
population of subjects. (revised per Amendments 01 and 04)  
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild to 
moderate AD to determine whether the effects of E2609 in this later stage population are 
comparable with those established in the MCI/Prodromal population within this same study 
(see Section 9.2.3 for discussion of the Bayesian design used in this study). (revised per 
Amendment 01)  
Immunological and hematological parameters will also be assessed.  (revised per 
Amendment 04)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of 
well-established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (Section 9.4.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; and a cognitive 
and functional assessment, which is the change from baseline in the derived ADCOMS at 
18 months of treatment in mild to moderate AD subjects.  (revised per Amendments 01
and 02)  Exploratory endpoints including assessments of efficacy, safety and other 
biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups (Section 9.7.4)  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
Page 769 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 51 of 160
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 
2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
Page 770 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 52 of 160
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild to moderate AD will be assessed as a “nested” population that does not 
follow the Bayesian adaptive design.  It was not considered appropriate to have a Bayesian 
design for both cohorts as this would have substantially increased the overall study sample 
size, delayed analyses of dose response, and would have added background “noise” for the 
comparison of subjects with MCI/Prodromal AD compared with those with mild to moderate 
AD. Data from each cohort will be analyzed independently for the purposes of decision 
making.  A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild 
to moderate AD confounding the results for the primary population (MCI/prodromal).  
(revised per Amendment 01)  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975)
Page 771 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 53 of 160
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)
Page 772 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 54 of 160

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (t-tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both t-tau and p-tau are sensitive markers of axonal and neuronal degeneration (t-tau) and 
neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel with 
disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have been 
correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful predictors 
of cognitive decline and progression to dementia due to AD.  Rebalancing dysregulated 
amyloid production early in the process may positively affect the neurodegenerative process 
and thus affect these markers and benefit the disease trajectory.  Therefore, monitoring these 
markers in conjunction with amyloid imaging may provide further supportive evidence of 
disease modifying effects.  (revised per Amendment 04)
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Page 773 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 55 of 160
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted on subjects with Screening PET scans performed for this study 
(ie, historical scans cannot be used for the longitudinal analyses) and will only be conducted 
until 18-month PET scans of acceptable quality have been obtained for at least 25 subjects 
per treatment arm for each amyloid PET ligand used.  (Revised per Amendment 02)
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
regions during the early stages of disease and progresses towards the anterior regions of the 
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF t-tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Page 774 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 56 of 160
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Two-stage study design:  there will be a pause in recruitment after approximately 
60 subjects (±20%) have been randomized to study drug (Stage A).  Only after the safety 
of E2609 in these Stage A subjects (consisting of up to 12 weeks data for the later 
subjects and longer dosing periods for the earlier subjects) has been reviewed by the 
DSMB and considered acceptable, will randomization of further subjects into the study 
commence (Stage B). (revised per Amendments 01 and 04)

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and percentage 
change from baseline), skin rash, reoccurrence of herpes virus infections including any 
oral herpes, genital herpes or shingles, other infections, MRI changes, ECGs, and 
pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be 
questioned on the frequency and impact of these events.  To assess potential 
Page 775 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 57 of 160
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and post-treatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood and DNA samples will be taken and stored for all subjects, 
and CSF samples will be taken and stored for all subjects who consent to CSF sample
collection (revised per Amendment 02).  These samples may be tested in the event that a 
subject develops AEs that warrant further investigation (eg, if a subject develops a 
treatment-emergent infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals
during the Treatment Period, and at the final Follow-Up Visit.

Full neurologic examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurologic examinations.  Details of the neurologic
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using the 
detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, Baseline,
and at regular intervals during the Treatment and Follow-Up
Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 4 off-treatment Follow-Up visits 
(2, 4, 8, and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated. (revised per Amendment 04)

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will randomize approximately 60 (±20%) eligible MCI/Prodromal or mild to 
moderate AD subjects at approximately 35 sites in the United States (revised per 
Amendments 02 and 04).  There will be no restriction to the number of subjects from either 
Page 776 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 58 of 160
population.  Stage B will randomize subjects at approximately 125 sites globally.  
Recruitment will continue in Stage B until a maximum of approximately 500 MCI/Prodromal 
subjects and up to a maximum of approximately 200 mild to moderate AD subjects have 
been randomized (including subjects randomized during Stage A).  The final total number of 
MCI/prodromal subjects will depend upon whether the prespecified criteria for either early 
success or futility are met.  The number of mild to moderate AD subjects randomized in 
Stage B will depend upon the number of mild to moderate AD subjects randomized during 
Stage A. (revised per Amendment 01)
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Required at Screening Visit 1:  
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT. Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
Page 777 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 59 of 160
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
Page 778 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 60 of 160
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
Page 779 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 61 of 160
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
Page 780 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 62 of 160
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
Page 781 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 63 of 160
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.

(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).  (revised per Amendment 04)
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (see 
Section 9.1.2.3). Subjects who discontinue study drug prematurely will also be scheduled to 
return to the study site for each scheduled visit when clinical efficacy assessments are to be 
conducted (ie, at Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been 
performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, 
FAQ, CBB and ISLT) will be conducted.  Regularly scheduled clinical efficacy visits do not 
need to be attended if they fall within 8 days (visit window) after the Early Discontinuation 
Visit or within ±8 days ofFollow-Up Visit 19 orVisit 20.  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. (revised per Amendment 04)
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Page 782 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 64 of 160
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test but who 
has no clinical signs or symptoms of infection, will have study drug temporarily 
suspended for at least 2 weeks but no more than 4 weeks.  During this period of study 
drug suspension, lymphocyte subset counts and complete blood count (CBC) with 
differentials will continue to be tested weekly until CD4 (T helper cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) have all returned to greater than the population-adjusted 
LLN after which time study drug can be resumed.  Testing of lymphocyte subset counts 
and CBC with differentials is required weekly for 4 weeks following resumption of study 
drug administration.  Temporary suspension and rechallenge with study drug is only 
permitted once for any given subject.  If the lymphocytes and CD counts do not return to 
greater than the population-adjusted LLN within 4 weeks from the start of temporary 
suspension the subject will need to be permanently discontinued from study drug.  
(revised per Amendment 04)
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendments 02 
and 04)  During the early stages of the treatment period, where visits are conducted 
weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already scheduled to be 
measured on a weekly basis and so additional visits or blood draws are not required.  
(revised per Amendment 02)  For these subjects, the decision as to whether the subject 
remains on study drug or is to be discontinued from study drug will be based upon 
clinical judgment and will take into account any clinical presentation in addition to the 
lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Page 783 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 65 of 160
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue, 
discontinue, or temporarily 
suspend study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts below 
discontinuation threshold and no clinical signs 
or symptoms of infection
Retest within 1 week along 
with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
temporarily suspend study 
drug for between 2 and 
4 weeks.  Continue weekly 
testing of lymphocyte subsets 
and CBC with differentials.  
Rechallenge with study drug 
allowed when CD4 (T helper 
cells), CD8 (cytotoxic 
T cells), and CD19 (B cells) 
absolute counts all greater 
than population-adjusted 
LLN.  Temporary suspension 
and rechallenge permitted 
only once for each subject.
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold
Lymphocyte subset counts 
(and CBC with differentials) 
to be performed weekly until 
lymphocyte subset counts 
return to ≥ population-
adjusted LLN 
Decision will be based upon 
lymphocyte subset counts 
and clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  
(Table revised per Amendments 02 and 04)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds, subjects with infections of moderate intensity will be 
discontinued from study drug (eg, subjects whose infections are not localized, or subjects 
who are systemically unwell, or who require systemic anti-infective drug treatment).   All 
subjects with infection who are discontinued from study drug will be followed for a 
period of 12 weeks or until the infection resolves/ stabilizes or until the CD4 (T helper 
Page 784 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 66 of 160
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have returned to 
greater than population-adjusted LLN (whichever comes latest).
(revised per 
Amendments 02 and 04)
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts below 
discontinuation threshold
If confirmed with 
repeat testing within 
1 week, then 
temporarily suspend 
study drug as per 
instructions above.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts between 
population-adjusted LLN and 
discontinuation threshold 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 
(cytotoxic T cells), or CD19 
(B cells) absolute counts always >
population-adjusted LLN 
May continue 
treatment with study 
drug unless 
discontinuation is 
clinically indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  
(Table revised per Amendments 02 and 04)
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
Page 785 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 67 of 160
discontinuation and will attend the Follow-Up Visits 2, 4, 8, and 12 weeks after the last 
dose of study drug.  They will also undertake an Unscheduled Visit (with MRI) at 
approximately 4 weeks after the visit at which such MRI features were first identified.  
An MRI will also be performed at approximately the time of the final Follow-Up Visit
(Visit 20).  Additional visits for safety may be arranged if clinically indicated in the 
opinion of the investigator, including after 12 weeks after the last dose of study drug.  At 
any time during the treatment period, subjects who have asymptomatic, treatment-
emergent microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.  
(revised per Amendment 04)
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered in Stage A and Stage B are shown below and in Figure 1.
The 2 highest E2609 doses (15 and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A, will be used for the mild to moderate AD population in Stage B.  
(revised per Amendment 01)  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo.
(revised per Amendment 01)  
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Page 786 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 68 of 160
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5, 15, 50 mg, or placebo.  The tablets 
will be supplied by the Sponsor in labeled blister packs.  The product release certificates for 
E2609 and placebo will be included in the clinical study report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)
Page 787 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 69 of 160

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for Stage A (all subjects), for Stage B MCI/Prodromal subjects and Stage B for mild to 
moderate AD subjects are described in Section 9.4.1. (revised per Amendment 01)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study 
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Page 788 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 70 of 160
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma 
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1 
Activity
% Reduction 
CSF A(1-x)
5 
6.2
3.3
80.3
16.2
33
15 
18.6
10
240.9
36.6
56
50 
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = beta-amyloid converting enzyme, CSF = cerebrospinal fluid, Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from 
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1 
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients.  (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 
400 mg (17.3% decrease).  No subject had infections or drug rash while receiving E2609 
100 mg QD or at lower doses in Study 002, whereas at 200 and 400 mg QD, 4 subjects had 
symptomatic orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The 
highest dose for Study 202 of 50 mg QD (tablet administered with food) is therefore 
expected to have a similar or better safety profile compared with the 100 mg QD capsule 
(administered fasted) in Study 002.  Specific exclusion criteria, blinded and unblinded safety 
monitoring procedures, and safety criteria for discontinuation from study drug are included in 
this study in order to mitigate any immunology-related risk with E2609, particularly in light 
of the progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
In Stage A, all subjects will be randomized to receive either placebo or E2609 at 5, 15, or 
50 mg QD.  In Stage B, subjects in the MCI/Prodromal cohort will continue to be 
randomized to receive either placebo or E2609 at 5, 15, or 50 mg QD. In Stage B, subjects in 
the Mild to Moderate AD cohort will be randomized to receive either placebo or E2609 at 
15 or 50 mg QD, but not the 5-mg QD dose.  The rationale for not including an E2609 5-mg 
QD dose in the dose regimens for Stage B subjects with mild to moderate AD is that more 
Page 789 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 71 of 160
advanced disease may require greater reduction in CSF Aβ levels for comparable effects. 
(revised per Amendment 01)  
Interim analyses of the E2609 plasma PK for all subjects and the E2609CSF PK and PD 
profiles will be performed on baseline data and samples collected after at least 4 weeks of 
study drug.  These interim analyses, as well as analyses of safety data, will be performed on 
an ongoing basis throughout Stage A.  Refer Section 9.7.3 for more detail. The median and 
mean percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment 
for each dose of E2609 and its 90% confidence interval for the median will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data from Stage A and will relate the average steady state plasma 
concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline after 
4 weeks of dosing.  (revised per Amendments 01, 02, 03, and 04)
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects, caregivers/informants, and 
all clinical site personnel involved with the conduct and interpretation of the study, including 
investigators will be blinded to the treatment codes (double-blind).  In order to make 
decisions about the remainder of the study as well as the full E2609 clinical development 
program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and perform 
interim analyses of these data.  (revised per Amendment 03)  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
Page 790 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 72 of 160
The PK/PD interim analyses will take place throughout the study as per Amendment 03 and 
will be conducted by an independent PK/PD scientist at the sponsor.  Any additional changes 
to dose required for this study will be reflected in a further amendment to the protocol and 
the Statistical Analysis Plan will detail how data will be handled in the primary analysis. 
(revised per Amendments 02 and 04)
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1 through Listing 5.  Medications that are permitted with 
restrictions are listed in 6 through Listing 8. (revised per Amendment 04)
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  (revised per 
Amendment 04)

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization
Page 791 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 73 of 160

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization.  However,
during the treatment period of the study, short term (not more than 14 days) use of 
steroids up to the equivalent of prednisolone 40 mg once daily is permitted after 
discussion with the Medical Monitor. Dosing with study drug should be suspended from 
the time steroid treatment is started. Complete blood count and lymphocyte subsets 
should be determined prior to starting steroid treatment and continue to be monitored 
weekly. Study drug may be resumed after discussion with the Medical Monitor when the 
following conditions are met: (1) treatment with steroids has been completed for at least
1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which 
required treatment with steroids has improved or resolved.  Weekly testing of lymphocyte 
subset counts and CBC with differentials is required for 4 weeks following resumption of 
study drug administration.  (revised per Amendment 04)
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed.  Subjects who are on anticoagulants may have a variable dose but should have 
stable anticoagulation control for at least 4 weeks before randomization. They may be 
required to stop their anticoagulant medication prior to CSF collection and then restart 
this medication after the LP procedure, as per local guidelines.  (revised per Amendment 
04)

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
Page 792 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 74 of 160
Antiplatelet therapy:  (revised per Amendment 04)

For subjects who consent to CSF sample collection:  Either aspirin or clopidogrel (or any 
other antiplatelet drug which is not aspirin) are permitted in all subjects.  Aspirin and
clopidogrel (or any other antiplatelet drug which is not aspirin) in combination are also 
permitted but subjects who are on such a combination of antiplatelet drugs may be 
required to stop 1 or more of these antiplatelet drugs before the LP procedure and restart 
after the LP as per local guidelines.   

For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, are permitted.   
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
Page 793 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 75 of 160
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study 
drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator (or if regionally required, the head of the medical institution or the 
designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
Page 794 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 76 of 160
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination (including the Brief Smell Identification Test [Sensonics Inc.]). (revised per 
Amendment 04).  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
Page 795 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 77 of 160
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  At the Screening Visit, the recommended order of 
assessments is: MMSE, ISLT (immediate recall), CBB, ISLT (delayed recall), CBB (repeat 
CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the 
assessments are to be conducted in the following order: MMSE, CDR, ADAS-cog14, FAQ,
ISLT (immediate recall), CBB, and ISLT (delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild to moderate AD.  (revised per Amendment 01)  
It also shows sensitivity to treatment effects with AChEIs.  The ADCOMS assesses both 
cognitive and functional domains and can be offered as a single primary clinical endpoint.  
The ADCOMS has a range from 0 to 1.97.  
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
Page 796 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 78 of 160

Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.

Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.

One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.

One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
ISLT: The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects are read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:  The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire: The caregiver or informant provides performance 
ratings (from 0 to 3) on 10 complex activities of daily living performed within the preceding 
4 weeks.  Scores range from 0 (independent) to 30 (dependent).  (revised per Amendment 04)
Page 797 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 79 of 160
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects. (revised per 
Amendment 04)
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of E2609.  For 
subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of E2609 concentrations. 
(revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with E2609.
Page 798 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 80 of 160
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A 2nd PK blood sample will be collected as close as possible in time to the 
LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the 1st report of an SAE or severe unexpected AE 
and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal (Section 9.5.1.3.3).  The timing of the Baseline LP needs 
to be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization 
timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  (revised per Amendment 04)  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 levels and activity.  (revised per 
Amendment 04)
Subjects who initially consented to CSF collection and provided a baseline CSF sample but 
did not provide a postrandomization sample will be approached to consider reconsenting to 
Page 799 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 81 of 160
postrandomization CSF sample collection even if they are beyond Week 5 (Visit 7); 
however, subject reconsent to this procedure is optional for these subjects.  (revised per 
Amendment 04)
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses.  Aβ(1-x) in both CSF and plasma will be measured using a modified 
commercially available enzyme-linked immunosorbent assay (ELISA).  The pre- and 
postscreening analysis of CSF Aβ(1-42), Aβ(1-40), t-tau, and p-tau will be performed using 
commercially available ELISAs.  (revised per Amendment 04)  BACE1 levels will be 
measured using internally developed fluorescence resonance energy transfer and ELISA 
based assay(s).  Substrates of BACE1 inhibition may also be explored using Western blots or 
other amenable methodology if clinical observations warrant and if analytes can be reliably 
tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
For subjects who consented to CSF sample collection, CSF samples from the Baseline Visit 
will also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, 
but not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, 
or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
Page 800 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 82 of 160
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of treatment (or at ED, providing the subject has received at least 
39 weeks of study drug).  Longitudinal amyloid PET imaging will only be conducted on 
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses) and will only be conducted until acceptable 18-month
PET scans have been obtained for at least 25 subjects per treatment arm for each amyloid 
PET ligand used (Table 6).  (revised per Amendment 02)  PET scanning will be performed 
with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and post-treatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
Page 801 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 83 of 160
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not necessary 
to report every sign or symptom as a separate AE if the overall disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, discontinuation of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  For subjects 
who discontinue early from study drug but undertake further efficacy assessments, AEs will 
only be collected for 3 months after the last dose of study drug, ie, through to the final
follow-up visit (Visit 20).  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
collected for 3 months after the last dose of study drug, ie, through to the final Follow-Up 
visit (Visit 20).  For subjects who discontinue early from study drug but continue with further 
efficacy assessments, SAEs will be solicited only for 3 months after the last dose of study 
drug (ie, up to the final follow up visit [Visit 20]). However, any SAEs volunteered by 
subjects after this time point must be reported according to standard procedures.  (revised per 
Amendment 04)
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADAS-cog14, MMSE, ISLT and CBB (see 
Page 802 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 84 of 160
Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment Period, 
and if this cognitive decline is considered by the investigator to be excessive relative to the 
subject’s recent AD history, this finding should be reported as an AE.  
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following AEs will require the collection of information sufficient to provide a detailed 
description of the event, treatment and outcome to the Medical Monitor for the study: any 
treatment-emergent significant laboratory abnormality; any seizures, herpes zoster infection, 
severe infection; any moderate to severe drug rash or any rash lasting more than 72 hours 
(regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the final Follow-Up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. (revised per Amendment 04)
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Page 803 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 85 of 160
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death
Page 804 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 86 of 160

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.  
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
Page 805 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 87 of 160
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening and Baseline only)  (revised per Amendment 02)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte T and B cell subset analyses (see Table 5).  Regulatory T cells (revised per 
Amendment 04)
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HbsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (including but not limited to CD3, CD4, CD8, CD45, CD19, 
CD16, CD56, and CD14) and total lymphocyte counts will be measured in order to provide 
the lymphocyte subset data as shown in Table 5.  In addition, Regulatory T cells will be 
measured.  Current sponsor data supports the literature showing there is an age-related 
decline in lymphocyte subsets (see Appendix 5). These data have been used to revise the 
LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts 
to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively) (revised per 
Amendments 02 and 04).  
Page 806 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 88 of 160
Table 5
Lymphocyte Subtypes Inclusive in BD Trucount™
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
(Table 5 revised per Amendment 04)
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
Page 807 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 89 of 160
in the supine position for at least 5 minutes.
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2 Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, and 18 and at the final Follow-Up Visit 
(Visit 20).  (revised per Amendment 04) In the event of an Unscheduled Visit, the 
investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already 
performed during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and 4 Follow-Up Visits at 2, 4, 8 and 12 weeks 
after the last dose of treatment.  (revised per Amendment 04) Subjects will also undertake an 
Page 808 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 90 of 160
Unscheduled Visit (with MRI) at approximately 30 days after the visit at which such MRI 
features were first identified.  Additional visits may be arranged if clinically indicated in the 
opinion of the investigator, and may occur later than 12 weeks after the final dose of study 
drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve; the Brief Smell Identification Test (Sensonics 
Inc.) will be administered at the same visits to objectively test olfaction.  Treatment-emergent 
abnormal neurological findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 809 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 91 of 160
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 810 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 92 of 160
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary)a
X
X
Demographics
X (Tier 1)
Medical historyb
X (Tier 1)
Prior / concomitant medicationsc
X (Tier 1)
X
Vital signs including weightd
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTe
X (Tier 1)
X
MMSEe
X (Tier 1)
X
CDRe
X (Tier 1)
X
FAQe
X (Tier 1)
X
ADAS-cog14
e
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGf
X (Tier 2)
X
Blood and urine for clinical laboratory testsg
X (Tier 2)
X
Blood for lymphocyte subset analysesh
X (Tier 2)
X
Blood for Ig analysesi
X (Tier 2)
X
Blood for viral screenj
X (Tier 2)
Blood for thyroid function testsk
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIl
X (Tier 3)
Amyloid PET scanm
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagea
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
(Table revised per Amendments 02 and 04)
Page 811 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 93 of 160
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
Subjects who initially consented to CSF collection and provided a baseline CSF sample but did not provide a 
postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample collection 
even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects.  
For those subjects who do consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or 
at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to 
be scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each individual subject. If the 
LP and cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used 
for PK and PD assessments.  A CSF sample will also be stored for testing in the event that the subject develops 
TEAEs that warrant further investigation (eg, treatment-emergent infection). (revised per Amendments 01, 02, and 
04) 
b:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization 
can be extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety 
laboratory tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
c:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
d:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
e:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At 
the Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times 
if required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
Page 812 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 94 of 160
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
f:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
g:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
h:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD19 (B cells), CD16/CD56 (natural killer cells) and CD14 (macrophages).  
Regulatory T cells will also be measured.  Viability staining may also be employed.  Whenever unscheduled 
lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a CBC with 
differentials, must also be repeated.  (revised per Amendments 02 and 04)
i:
Igs to be analyzed include IgG, IgA and IgM.
j:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
k:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine, and free thyroxine.
l:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
m:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the 
previous 12 months and provided that the scan and result are considered acceptable by the central PET reading group.  
(revised per Amendment 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops TEAEs that warrant further 
investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject 
already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurologic examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.  The Brief Smell 
Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of the neurological
examination. (revised per Amendment 04)
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 813 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 95 of 160
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological assessment via 
photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Blood samples (lymphocyte subset 
analyses)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Blood samples (Igs)m
X
X
X
X
X
X
X
X
X
X
X
Blood samples (isolation of PBMCs)
X
X
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample (storage for immune status)o
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Page 814 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 96 of 160
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
W2
19c
W8
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
561
575
589
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
81
83
87
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
80
82
86
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Blood samples for PD and exploratory 
biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 815 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 97 of 160
Footnotes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled, W2 = new Week 2 follow-up visit, W8 = new Week 8 follow-up visit.  (revised per Amendment 04)
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 2, 4, 8, and 12 weeks after the last dose of study drug (Visit W2, 19, W8, and Visit 20, respectively).  Subjects who discontinue study drug prematurely will 
also be scheduled to return to the study site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these 
visits have not already been performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB, and ISLT) will be conducted.  Regularly 
scheduled clinical efficacy visits do not need to be attended if they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days of Follow-Up 
Visit 19 of Visit 20).  Subjects who discontinue early from study drug are considered on study as long as they return for their regularly scheduled clinical efficacy visits as 
outlined above. (revised per Amendment 04)  
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 4 post-treatment Follow-Up visits; 2, 4, 8, 
and 12 weeks after the last dose of study drug (Visits W2, 19, W8, and 20, respectively).  If clinically indicated, more frequent safety assessments can be made as UNS 
assessments or visits during the post-treatment Follow-Up period.  (revised per Amendment 04)
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at the previous Follow-Up visit.  (revised per Amendments 02 and 04)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history. The Brief Smell Identification Test (Sensonics Inc.) will be administered at the same visits and serves as part of 
the neurologic examination. (revised per Amendment 04)
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
Page 816 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 98 of 160
Footnotes for Table 7
l:
Lymphocyte subsets will include but are not limited to the following cell surface marker assessments: CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [NK cells] and CD14 [macrophages]) and total lymphocytes.  Regulatory T cells will also be measured. Viability staining may also be employed.  Whenever 
unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be 
performed along with assessment of AEs. (revised per Amendments 02 and 04)
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops a TEAE that warrant 
further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective 
agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors.  
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within the 
7 days before Visits 14, 16, 18, and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will be 
collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14, and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  Postrandomization CSF sample collection is scheduled at Visit 7 (or later postrandomization timepoint) and Visit 18/ED.   
If a postrandomization CSF sample is collected later than Visit 7, time-matched plasma PK samples are also required (see Footnote t).  All visits at which CSF samples are 
scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. The timing of the Baseline LP needs to be 
Page 817 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 99 of 160
Footnotes for Table 7
scheduled carefully such that subsequent LPs (Visit 7 [or later postrandomization timepoint] and Visit 18) can be performed between 4 and 8 hours postdose and at a similar 
time of day (±1 hour) for each individual subject.  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity 
drip collection method must be used.  If the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been completed
and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical observation.  The 
CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already stopped study drug, then 
no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. . Subjects who initially consented to CSF 
collection and provided a baseline CSF sample but did not provide a postrandomization sample will be approached to consider reconsenting to postrandomization CSF sample 
collection even if they are beyond Week 5 (Visit 7); however, subject reconsent to this procedure is optional for these subjects. (revised per Amendments 01, 02, and 04)  
w:
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 818 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 100 of 160
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.5.2, and Figure 2.
See Section 9.5 for a full description of the procedures and assessments to be performed 
during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
20
2 x 5 mL
18 x 5 mL
100 mL
Lymphocyte subset analysesa
20
2 x 4 mL
18 x 4 mL
80 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
10
2 x 2 mL
8 x 2 mL
20 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
342 mL
422 mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 819 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 101 of 160
a:
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, 
a CBC with differentials must also be performed. Therefore, for each unscheduled or repeat test, an additional 9 mL 
will be collected (5 mL for hematology and 4 mL for lymphocyte subset analyses) 
(Table 8 revised per Amendment 04)
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose
of study drug, ie, through to the final follow-up visit (Visit 20).  (revised per Amendment 
04) In subjects who discontinue study drug early, but continue with efficacy assessments, 
SAEs only need to be solicited up to 3 months after the last dose of study drug.  However, 
any SAEs volunteered by subjects after this time point must be reported according to 
standard procedures.  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.
Page 820 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 102 of 160
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
9.5.4.3
Reporting of Events Associated with Special Situations
Page 821 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 103 of 160
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
Page 822 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 104 of 160
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 2, 4, 8, and 12 weeks after the last dose of study 
drug (Visits W2, 19, W8, and Visit 20, respectively) (see Section 9.1.2.3).
(revised per 
Amendment 04) See Table 7 for full details of the assessments to be performed at these 
visits.  Subjects who discontinue study drug prematurely will also be scheduled to return to 
the study site for each scheduled visit when clinical efficacy assessments are to be conducted 
(ie, at Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At 
these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and 
ISLT) will be conducted.  Subjects who discontinue early from study drug are considered on 
study as long as they return for their regularly scheduled clinical efficacy visits as outlined 
above. Subjects who discontinue study drug early (as opposed to subjects whose dosing with 
study drug is temporarily suspended under Medical Monitor guidance) will not be permitted 
to restart study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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.  
Page 823 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 105 of 160
Subjects who withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Abuse or Diversion of Study Drug eCRF. (revised per 
Amendment 04)
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
Page 824 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 106 of 160
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
Page 825 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 107 of 160
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal subjects 
as measured by vMRI 

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects
(revised per Amendment 01)  
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01, 02, and 04)  
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD 
subjects as measured by vMRI

CSF Aβ(1-x) and Aβ(1-42) after at least 4 weeks and at 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild to moderate AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months 
of treatment, and during post-treatment follow-up in MCI/Prodromal and mild moderate 
AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and 
mild to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD 
subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.
Page 826 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 108 of 160

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who sufficiently 
comply with the protocol.  The PP Analysis Set will be used to conduct a sensitivity 
analysis of the primary efficacy endpoint.  Details of the evaluability criteria will be 
determined before database lock and treatment unblinding, and will be specified in the 
statistical analysis plan.

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
Page 827 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 109 of 160
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014 or higher).  
(revised per Amendment 04) The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the Safety Analysis Set by treatment group, 
Anatomical Therapeutic Chemical class, and WHO DD preferred term.  Prior medications 
will be defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the date of the last dose.  All medications will be 
presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy Analyses
The MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  

ED90:
The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria 
if the probability that the ED90 at 18 months of treatment achieves 25% improvement 
over placebo is at least 80%.  Early success is achieved before all MCI/Prodromal
subjects complete 18 months of treatment and can only be determined after at least 
200 MCI/Prodromal subjects have been randomized.  If early success is declared before 
Page 828 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 110 of 160
full randomization, the randomization of new MCI/Prodromal subjects will stop but 
subjects already randomized into the study will receive the full 18 months of treatment 
(following confirmation from the Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if 
the probability that the ED90 is better than placebo by the clinically significant difference
of 25% is less than 5% at 18 months of treatment.  The statistical futility boundary is 
binding; if the statistical futility boundary is crossed the study will be considered to have 
failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if 
an ED90 at 18 months treatment has at least an 80% probability of achieving 
25% improvement over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
All mild to moderate AD subjects will be included in the efficacy evaluations of the Mild to 
Moderate AD cohort.  The analysis of the Mild to Moderate AD cohort is based on the group 
sequential design.  Interim analyses in the Mild to Moderate AD cohort will only be 
performed after the MCI/Prodromal cohort crosses the early success boundary.  The early 
efficacy signal based on the change from baseline of ADCOMS at 18 months is defined as 
crossing the interim-analysis boundaries for overwhelming efficacy in the mild to moderate 
AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha 
spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and 
final analyses, respectively, according to 2 planned interim analyses at the 60% and 
80% information fraction. (revised per Amendment 01)  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
Page 829 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 111 of 160
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Sensitivity analysis of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the PP set and as such, no multiplicity adjustments will be 
made to account for the interim analyses.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint:
(revised per 
Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
Page 830 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 112 of 160
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild to moderate AD.  If there is no treatment group-by-population interaction 
in the overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild to 
moderate AD) in the overall study.  Otherwise, the MMRM analysis will only include 
subjects in the Mild to Moderate AD cohort.  The comparison between placebo and active 
doses will be performed within mild to moderate AD subjects regardless of subjects included 
in the MMRM analysis.  Dunnett’s method will be used to control for multiplicity due to 
multiple comparisons.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01, 02, and 04)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild 
to moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to 
moderate AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after at least 4 weeks and at 
18 months in MCI/Prodromal and mild to moderate AD subjects.  Data from early 
discontinuations will also be included. (revised per Amendment 04)

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, CBB, 
and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal and 
mild to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 
4 weeks and 18 months of treatment, and during post-treatment follow-up in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild to 
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months 
in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
Page 831 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 113 of 160
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD 
subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 
12 and 18 months in MCI/Prodromal and mild to moderate AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for E2609 concentration listings and for summaries of 
E2609 concentrations in plasma and CSF by dose and day.  E2609 metabolite PK data may 
also be listed and summarized. (revised per Amendment 04)
A population PK approach will be used to characterize the plasma PK of E2609.  For this 
approach, plasma PK data from this study will be pooled with relevant data from Phase 1 
studies.  As appropriate, the effect of covariates on the PK of E2609 will be evaluated.  The 
PK model will be parameterized for oral clearance (CL/F) and apparent volume of 
distribution (Vz/F) for E2609. Derived exposure parameters such as steady state area under 
the concentration time curve (AUC) and average concentration (Cavg) of E2609 and other 
derived parameters will be calculated from the model using the individual estimates 
parameterized for oral clearance and dosing history.  (revised per Amendment 04)
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Page 832 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 114 of 160
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  The percentage change from baseline in CSF 
Aβ(1-x), Aβ(1-42), Aβ(1-40), t-tau, p-tau, and BACE1 variables (eg, activity and protein 
levels) after at least 4 weeks and at 18 months will be analyzed and presented graphically.
Baseline levels and changes in t-tau and p-tau will be correlated with changes in CSF 
Aβ(1-42), imaging markers, and ApoE4 status.  (revised per Amendment 04)  
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels, amyloid load on PET, vMRI, and 
E2609 dose, plasma, and CSF exposure will be initially explored graphically and any 
emergent relationship will be explored through population PK/PD modeling. The PK/PD 
relationship between plasma PK parameters with other biomarkers may also be explored 
using similar methods.  (revised per Amendment 04)  
The relationship between plasma and CSF exposure to E2609 and the clinical efficacy scales 
(eg, MMSE, CDR) will be explored graphically.    Additionally, the relationship between 
plasma exposures of E2609 and select lymphocyte parameters will be explored graphically, 
and any emergent relationship will be explored using population-based modeling methods.  
(revised per Amendment 04)  
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
Page 833 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 115 of 160
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
Page 834 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 116 of 160
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets measured (including but not limited to CD4 [T helper cells], CD8 
[cytotoxic T cells], CD19 [B cells], CD16/CD56 [natural killer cells] and CD14 
[macrophages] and regulatory T cells) will be summarized in the same manner as other 
Page 835 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 117 of 160
laboratory parameters.  Mean lymphocyte subsets and the mean change from baseline in 
lymphocyte subsets will also be displayed graphically over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE,
CDR,
and CBB 
(Section 9.7.1.6).
Page 836 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 118 of 160
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Page 837 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 119 of 160
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 
0.15 (SUVR), respectively; this would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per 
Amendment 01)  
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in Section 9.7.1.6.2.  
The statistical power was estimated through simulation for the dose-response assumption that 
the percent reduction in change from baseline of ADCOMS at 18 months compared with 
placebo would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated 
power for the actual planned 200 mild to moderate AD subjects is approximately 80% 
assuming a 2-sided alpha of 0.05.  (revised per Amendment 01)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis 
and perform interim analyses of these data.  Investigators, other clinical site staff, subjects 
and caregivers/informants will remain blinded to study treatment.  (revised per 
Amendment 03)
An interim safety analysis will also be conducted when the Stage A subjects have completed 
12 weeks of treatment (or discontinue study drug early) in Stage A.
(revised per 
Amendments 01, 03, and 04)  
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of 
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
Page 838 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 120 of 160
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, including MCI/Prodromal subjects from 
Stage A and Stage B).  (revised per Amendment 01)  Further interim efficacy analyses will 
be conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, and 
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
Page 839 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 121 of 160
The Mild to Moderate AD Cohort (revised per Amendment 01)  
A group sequential design will be used for the Mild to Moderate AD cohort.  (revised per 
Amendment 01)  This design includes 3 looks, 2 interim looks (when 60% and 
80% information fractions are achieved) and 1 final look.  The information fraction is the 
number of assessments in all treatment arms divided by the total number of expected 
assessments.  Interim analyses will be performed after the MCI/Prodromal cohort crosses the 
early success boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 
0.0423 for the first, second, and final analyses, respectively.  If the actual information 
fraction during the interim analyses is different from 60% or 80% at the interim, the efficacy 
boundaries will be adjusted based on the actual information fraction.  
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort 
based on the data for mild to moderate AD subjects available at that time. (revised per 
Amendment 01)  
Randomization into the Mild to Moderate AD cohort will remain at a fixed schedule 
throughout Stage B.  (revised per Amendment 01)  
The interim analyses in the Mild to Moderate AD cohort will be conducted by an
independent analysis group.  (revised per Amendment 01)  
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 
3 active doses for the first 100 MCI/Prodromal subjects randomized, including those 
randomized from both Stage A and Stage B).  Thereafter, randomization probabilities to each 
treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  (revised 
per Amendment 01)  
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)  
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 
dose groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to 
moderate AD subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 
50 mg E2609) at a 1:1:1 ratio. (revised per Amendment 01)  
Page 840 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 122 of 160
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 841 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 123 of 160
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Page 842 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 124 of 160
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology.
2007;68:1588-95.
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on 
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Page 843 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 125 of 160
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association 
workgroups 
on 
diagnostic 
guidelines 
for 
Alzheimer's 
disease.
Alzheimers Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Page 844 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 126 of 160
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 845 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 127 of 160
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 846 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 128 of 160
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 847 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 129 of 160
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 848 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 130 of 160
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 CTA 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 CTA 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 CTA 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.
Page 849 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 131 of 160
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.
Page 850 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 132 of 160
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5 g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Female:
>3.0 – 5.032
Female:
>5.0 – 20.032
Female:
>20.032
Page 851 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 133 of 160
Grade 1
Grade 2
Grade 3
Grade 4
Male:
>44 – 3.0 x 44
Male
>3.0 – 5.044
Male:
>5.0 – 20.044
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 852 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 134 of 160
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 853 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 135 of 160
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1 through Listing 5.  Medications permitted with 
restrictions are listed in Listing 6 through Listing 8.  (revised per Amendment 04) These may 
not be all-inclusive listings.  Please contact the medical monitor(s) if the investigators have 
any questions or concerns regarding any medication not listed that your subjects may be 
taking before enrollment or start during the course of the E2609-G000-202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 854 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 136 of 160
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Biaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 855 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 137 of 160
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 856 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 138 of 160
Listing 2 Prohibited Medications Within 5 Half-lives or 60 days, Whichever is Longer, 
Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa,b and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
b:
During the treatment period of the study, short term (not more than 14 days) use of steroids up to 
the equivalent of prednisolone 40 mg OD is permitted after discussion with the Medical Monitor. 
Dosing with study drug should be suspended from the time steroid treatment is started. Complete 
blood count and lymphocyte subsets should be determined prior to starting steroid treatment and 
continue to be monitored weekly. Study drug may be resumed after discussion with the Medical 
Monitor when the following conditions are met: (1) treatment with steroids has been completed 
for at least 1 week; (2) total lymphocytes not <LLN; (3) no lymphocyte subsets are below the 
discontinuation threshold; (4) the investigator considers that the medical condition which required 
treatment with steroids has improved or resolved.  Weekly testing of lymphocyte subset counts 
and CBC with differentials is required for 4 weeks following resumption of study drug 
administration.  (revised per Amendment 04)
Page 857 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 139 of 160
Listing 3 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 858 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 140 of 160
Listing 4 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 859 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 141 of 160
Listing 5
Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last 
Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 860 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 142 of 160
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Final Follow-Up Visit 
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 861 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 143 of 160
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, 
Oramorph SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
Page 862 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 144 of 160
Listing 7
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ®
or ™)
PRN = Pro re nata
Page 863 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 145 of 160
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 864 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 146 of 160
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Page 865 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 147 of 160
Listing 8
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 866 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 148 of 160
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 867 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 149 of 160
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 868 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 150 of 160
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 869 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 151 of 160
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Page 870 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 152 of 160
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Relaxed
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 871 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 153 of 160
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 872 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 154 of 160
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
Page 873 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 155 of 160
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or 
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)    
Page 874 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 156 of 160
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and Table
12), and a 10% cut value is applied to each of the 3 CD markers of interest the following 
age-adjusted LLN values are generated: 
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
Page 875 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 157 of 160
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 876 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 158 of 160
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 877 of 1658


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 159 of 160
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product 
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 878 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 04)
E2609-G000-202
Eisai
FINAL (v6.0):  29 Jun 2016
Confidential
Page 160 of 160
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof-of-Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 879 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page i of xiii
REVISION HISTORY
Revisions to Version 4.0
New version/date:  Version 5.0, 06 Feb 2016
Change
Rationale
Affected Protocol Sections
Add interim analyses of safety, 
and PK/PD data throughout 
Stage A 
Decision making 
regarding the remainder 
of the study and the full 
E2609 clinical 
development program

Synopsis –
o Study Design
o Interim Analysis
Section 9.1
Section 9.4.6
Section 9.7.3
Page 880 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page ii of xiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.6
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Section 12, Listing 2
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
tests repeated at the Baseline 
Visit.
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 
unnecessarily screening 
out subjects with 

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Page 881 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page iii of xiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce
subject burden.

Synopsis –
o
Inclusion/
Exclusion Criteria
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.5.3

Section 9.3.1

Section 9.5.2, Table 6 and 
Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2

Section 9.5.2, Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
Added to provide clarity 
for the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
from 30 to 40
For feasibility purposes

Synopsis – Sites

Section 6

Section 9.1
Page 882 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page iv of xiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1, Figure 2

Section 9.5.1.3.1

Section 9.5.2, Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3, Table 1

Section 9.5.2, 
o Table 6
o Table 7
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1, Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2, Table 6
Page 883 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page v of xiii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2, 
o Table 6
o Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3, Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2, Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2, 
o Table 6
o Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 884 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page vi of xiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1, Section 9.1.1

Figure 1

Section 9.2.1, Section 9.2.2, 
Section 9.2.3

Section 9.2.5.3 and Section 9.2.5.4

Section 9.3, Section 9.3.1, 
Section 9.3.2

Section 9.4.1, Section 9.4.3, 
Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2, Section 9.7.1.1.3

Section9.7.1.4

Section 9.7.1.6, Section 9.7.1.6.2, 
Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.2.2

Section 9.7.3

Section 9.7.4
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.1
Page 885 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page vii of xiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 
capacity to consent themselves.

Section 5.3
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis – Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Page 886 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page viii of xiii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis – Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 887 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page ix of xiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis - Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5.1 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis – Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis – Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
Inclusion/Exclusion  Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and 
International Normalized Ratio
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
Inclusion/Exclusion Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
For subjects who discontinue study 
drug prematurely, conduct efficacy 
To facilitate efficacy analyses, 
which are based on longitudinal 

Synopsis –Study Design 

Section 9.1.2.2

Section 9.3.3
Page 888 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page x of xiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
modeling for all subjects

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol. The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis - Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis - Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis – Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline,
during treatment, and posttreatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis - Assessments,

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 

Synopsis - Concomitant 
Drug/Therapy

Section 7.1
Page 889 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page xi of xiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
plasma levels of E2609

Section 9.4.7

Appendix 2(Listing 6)
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis – Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis – Analysis of 
Primary Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis – Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (exclusion criterion 8) but a 
blood draw for Vitamin B12 was 
inadvertently missed out of Table 6 
in protocol version 1.

Synopsis – Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5.1
Page 890 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page xii of xiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis – Study Endpoints

Section 9.7.1.2
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.6

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Page 891 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page xiii of xiii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 892 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 1 of 156
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and 
Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to 
Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
V5.0
06 Feb 2016 (Amendment 03)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 893 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 2 of 156
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, Dose-Finding 
Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive 
Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia Due to Alzheimer’s Disease (revised per Amendment 01)
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 40 sites, United States only (revised per Amendments 01 and 02)
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  Approximately 42 months from initiation of Stage B (revised per Amendment 01)
Phase 2
Objectives
Primary Objectives
1.
To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect (ED90)
for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 18 months of 
treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease (referred to as MCI/Prodromal throughout the protocol)
2.
To assess the safety (including immunological and hematological parameters) and tolerability of 
daily dosing with E2609 in MCI/Prodromal subjects and in subjects with Mild to Moderate 
Dementia due to Alzheimer's Disease (referred to as mild to moderate AD throughout the 
protocol) (revised per Amendment 01)
Secondary Objectives (revised per Amendment 02)
1.
To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects, as measured by volumetric magnetic 
resonance imaging (vMRI)
2.
To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 18 months 
in mild to moderate AD subjects (revised per Amendment 01)
Page 894 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 3 of 156
Exploratory Objectives
(revised per Amendments 01 and 02)
1.
To explore the effect of E2609 compared with placebo on the derived ADCOMS following 
12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2.
To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3.
To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects and in mild to moderate AD 
subjects (revised per Amendment 02)
4.
To explore the effects of E2609 compared with placebo on clinical status at various time points 
during 18 months of treatment, and during post-treatment follow-up, in MCI/Prodromal and mild 
to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional Activities 
Questionnaire)
f.
The International Shopping List Task (ISLT)
5.
To explore the effects of E2609 compared with placebo on various biomarkers in MCI/Prodromal 
and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after 18 months 
of treatment
b.
Plasma and CSF amyloid, and CSF β-amyloid converting enzyme 1 (BACE1) measurements
during 18 months of treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain volume and 
total ventricular volume at 6, 12, and 18 months of treatment and during posttreatment
follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission tomography 
(PET)
6.
To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and mild to 
moderate AD subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7.
To explore the relationship between the treatment effects of E2609 on the ADCOMS and its 
effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and mild to 
moderate AD subjects
Study Design
This will be a multicenter placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common set of inclusion 
criteria, consistent with the National Institute on Aging – Alzheimer’s Association (NIA-AA) clinical 
research criteria for Mild Cognitive Impairment (MCI) due to Alzheimer’s Disease (AD) or mild to 
moderate AD, will be required for all subjects.  In addition, the MCI due to AD population will also 
be consistent with the research criterion for “Prodromal AD” in that episodic memory will be 
impaired on a list learning task (ISLT).  As the non-demented subjects will be consistent with the 
criteria for both MCI due to AD and Prodromal AD they will be identified as MCI/Prodromal 
Page 895 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 4 of 156
subjects in this protocol. The diagnosis of MCI/Prodromal AD or mild to moderate AD will be based 
on both clinical and biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an interim 
evaluation of the safety and tolerability of chronic dosing with E2609 (after the first 60 randomized 
subjects have completed 12 weeks of treatment or have discontinued study drug early) before 
expanding enrollment to include a larger number of subjects in Stage B.  (revised per Amendment 01)
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective of 
whether they were recruited during Stage A or Stage B.  Bayesian response adaptive randomization 
will be used in the MCI/Prodromal cohort only during Stage B.  All mild to moderate AD subjects 
will be included in the efficacy evaluations for that cohort.  (revised per Amendment 01)
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if required
[revised per Amendment 02]) includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All 
screening assessments (within 4 distinct tiers) must be completed, and eligibility to continue in the 
study confirmed, before any baseline assessments commence.  Following successful completion of
the Prerandomization Phase, eligible subjects will be randomized and will enter the Randomization 
Phase, which will consist of 2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 
12 weeks).
Stage A
Stage A will be limited to approximately 40 sites in the United States. (revised per Amendments 01 
and 02)  Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 4 treatment groups within 
each of the 2 clinical populations.  (revised per Amendment 01) In addition to the placebo group, 
3 E2609 doses will be used to reduce CSF amyloid β levels by approximately 25% (5 mg), 50%
(15 mg), and 75% (50 mg) from baseline, respectively, at steady state.  PK/pharmacodynamic (PD) 
modeling has shown that these doses should achieve these targets when administered once daily (QD) 
with food, and these doses will be evaluated based on the 4-week assessment of CSF Aβ(1-x) from 
subjects who provide voluntary consent for CSF measurement.  (revised per Amendment 02)
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In addition, 
approximately every 3 months from the time the first subject is randomized during Stage A, an 
independent data safety monitoring board (DSMB; including at least 1 immunologist) will review all 
safety data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
review as to whether any change(s) to the study are necessary.  Unless the DSMB recommends 
otherwise, randomization of subjects into Stage A will continue until 60 subjects have been 
randomized and dosed.  (revised per Amendment 01)
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who consent to 
provide CSF samples at Baseline and after 4 weeks of study drug.  These interim analyses, as well as 
analyses of safety data, will be performed on an ongoing basis throughout Stage A.  Refer to the 
Interim Analysis section for more detail.  (revised per Amendment 03)  These data will be used to
evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions from baseline in 
CSF Aβ(1-x) levels.
(revised per Amendments 01 and 02)  The mean percentage change from 
baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of E2609 and its 
90% confidence interval will be derived.  In addition, exploratory PK/PD modeling will be 
conducted.  This PK/PD modeling will use the observed PK and PD data from Stage A and will relate 
the average steady state plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage 
reduction from baseline after 4 weeks of dosing.  (revised per Amendment 02)Once 60 subjects in 
Stage A have completed at least 12 weeks of treatment (or discontinued study drug early) an interim 
Page 896 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 5 of 156
safety analysis will be conducted by Eisai and the DSMB. (revised per Amendment 01) Subjects in 
Stage A will continue study drug while the DSMB reviews all the available safety data, but 
randomization of additional subjects will not take place (ie, recruitment into Stage B will not 
commence) until the safety analysis is completed by the DSMB.  
If there are safety signals with one of the E2609 dose groups that would require dose adjustment, 
changes to dose will be reflected in an amendment to the protocol.  Information on how these subjects 
will be handled in the primary analysis will be described in the Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  (revised per 
Amendment 02)  Stage B will enroll, randomize, and dose additional eligible subjects up to a 
maximum of 500 MCI/Prodromal and up to a maximum of 200 mild to moderate AD. The final total 
number of MCI/Prodromal subjects will depend upon whether the prespecified criteria for either early 
success or futility are met. (revised per Amendment 01) Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment to the study is completed; 
following this the DSMB will meet approximately every 6 months.  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort will 
include 3 doses of E2609 (5, 15, and 50 mg QD) whereas the Mild to Moderate AD cohort will only 
include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort only during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according to a 
fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  (revised per 
Amendment 01)   The remaining subjects in the MCI/Prodromal cohort in Stage B will then be 
randomized according to response adaptive randomizations based on the ADCOMS results using the 
Bayesian interim efficacy analyses.  The mild to moderate AD subjects will be randomized according 
to a fixed schedule (1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B. (revised per 
Amendment 01)
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also
be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when clinical 
efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18) if these visits have 
not already been performed.  At these visits, only the clinical efficacy assessments (MMSE, CDR,
ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  Subjects who discontinue early from study 
drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study 
drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after the last dose of 
study drug (Visit 19) and a second 12 weeks after the last dose of study drug (Visit 20).  If clinically 
indicated, more frequent safety assessments can be conducted as part of unscheduled visits during the 
posttreatment Follow-Up period.
Page 897 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 6 of 156
Number of Subjects

Stage A:  Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be 
screened to provide 60 randomized subjects (target of 15 subjects per treatment arm).  There 
will be no limit to the number of subjects randomized from either clinical cohort.  (revised per 
Amendments 01 and 02)

Stage B:  Up to approximately 2100 MCI/Prodromal subjects will be screened to provide up to 
500 randomized subjects.  The final number of MCI/Prodromal subjects will depend upon 
whether the prespecified criteria for either early success or futility are met.  In addition, up to 
approximately 835 subjects with mild to moderate AD will be screened to provide up to 
200 randomized mild to moderate AD subjects.  The final number of mild to moderate AD 
subjects randomized in Stage B will depend upon the number of mild to moderate AD subjects 
previously randomized during Stage A. (revised per Amendment 01)
Page 898 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 7 of 156
Inclusion Criteria
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01)
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on the 
ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted norms in 
delayed recall on the ISLT plus impairment of at least 1 SD from age-adjusted norms in at 
least 1 other computerized learning and memory test (ISLT immediate recall, or 1 of the
learning and memory components of the CBB). (revised per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Exclusion Criteria
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
Page 899 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 8 of 156
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and < 1cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures (revised per Amendments 01
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for the 
testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
Page 900 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 9 of 156
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled steroids 
need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded 
(topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL
respectively. (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings. (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
Page 901 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 10 of 156
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.
Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study treatment period and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study treatment period or for 28 days after study 
drug discontinuation.
Page 902 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 11 of 156

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the same 
contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or not practicing 
highly effective contraception throughout the study period or for 28 days after study drug 
discontinuation).  No sperm donation is allowed during the study period or for 28 days after study 
drug discontinuation.
Study Treatments
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets to match 
E2609 will be of identical appearance.  Each subject will receive 2 tablets, which when combined 
will make up the required doses of E2609 (see below) or placebo, to be administered orally QD with 
food.  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised per Amendment 01)

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised 
per Amendment 01)

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo.  
(revised per Amendment 01)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising: 

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, 
the duration of the pre-randomization phase can be extended by up to 4 weeks to allow 
additional time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Page 903 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 12 of 156
Concomitant Drug/Therapy
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit (see Appendix 2 for a detailed listing of 
these agents):  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives or 
7 days (whichever is longer) before randomization

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization

Live vaccines are not permitted within 3 months before randomization.  This does not apply 
to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be included in the 
primary analyses: 

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for the primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications that 
are administered as short courses of treatment or which are to be used intermittently as 
needed

Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a 
period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator,
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks.
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of selected 
items (12 total) from 3 fully validated and well established clinical tools, the ADAS-cog (4 items), 
the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should be administered in full in the 
Page 904 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 13 of 156
morning, or, if not possible, consistently at the same time of day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery: A computer-based battery comprising 4 cognitive tests:  
1.
Detection – a simple reaction time test.  Speed of response is the measure.
2.
Identification – a simple choice reaction time test.  Speed of response is the measure.
3.
One Card Back – a simple working memory test.  Accuracy of response is the measure.
4.
One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
International Shopping List Task: The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
Functional Assessment Questionnaire: The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.  Either a caregiver or informant or the subject provides performance 
ratings on 10 complex activities of daily living performed within the preceding 4 weeks.  
Volumetric Magnetic Resonance Imaging: vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood samples will be collected for the determination of the concentrations of E2609. For subjects 
who consent to CSF sample collection, CSF samples will be collected for the determination of E2609 
concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations may be 
performed depending on emerging data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Brain atrophy will be measured by vMRI: see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), total tau (t-tau), and p-tau will be measured in subjects 
who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and activity in 
CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers (eg, miRNA) may also be evaluated in plasma and/or 
CSF.
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group. (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses) and will only be conducted through to the time at which 
acceptable 18-month PET scans have been obtained for at least 25 subjects per treatment arm for each 
amyloid PET ligand used. (revised per Amendment 02)
Page 905 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 14 of 156
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4 homozygous 
or heterozygous status versus non-carriers and NAT2 status will be used in the statistical analysis to 
determine the effects on treatment response and safety.  Remaining genomic DNA may also be stored 
for up to 15 years to be used to examine the role of DNA sequence variability on the absorption, 
distribution, metabolism, and elimination of E2609, development of AEs, as well as the underlying 
AD.  Variations in E2609 exposure or the occurrence of AEs observed in the study population may be 
evaluated by correlation of single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and SAEs, monitoring of hematology, blood chemistry, and urinalysis, 
measurement of vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might indicate signals of 
possible drug abuse potential will require a more detailed follow-up.  Subjects reporting AEs relating 
to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of 
these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the first month, every 2 weeks for the next 2 months (Months 
2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be monitored 
every 3 months until the end of the Treatment Period and at both Follow-Up Visits.  Serum IgG, IgA, 
and IgM will be monitored monthly for the first 3 months, at 6, 12, and 18 months, and at both 
Follow-Up Visits.  
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects who consent to CSF sample collection (revised per 
Amendment 02).  These samples may be tested for exploratory biomarkers associated with study drug 
or disease, or in the event that a subject develops AEs that warrant further investigation (eg, to test if 
a subject with a treatment-emergent infection was exposed to any suspected infective agents before
treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurological examinations will be performed at Baseline, at 6, 12, and 18 months, and at both 
Follow-Up Visits, by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations.  The neurological examinations will include muscle strength 
Page 906 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 15 of 156
testing and assessment of cranial nerves including olfaction as well as other parts of the CNS.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF Aβ(1-42), tau, and 
p-tau will be performed using ELISAs.
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the Bayesian 
methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects
Secondary Endpoints
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal subjects as 
measured by vMRI

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects  (revised 
per Amendment 01)
Exploratory Endpoints
(revised per Amendments 01 and 02)
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to moderate 
AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD subjects 
as measured by vMRI
Page 907 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 16 of 156

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects and in mild to moderate AD subjects  (revised per Amendment 02)

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months: 
ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and mild to moderate 
AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months of 
treatment, and during posttreatment follow-up in MCI/Prodromal and mild to moderate AD 
subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and, 
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and mild 
to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic factors 
(including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD subjects
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose 
of study drug and have baseline and at least 1 postdose primary efficacy measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who sufficiently comply 
with the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian adaptive 
design.  Frequent interim analyses will be performed to assess the probability of early success and 
futility and to make early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the derived 
ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria if the 
probability that the ED90 at 18 months of treatment achieves 25% improvement over placebo 
is at least 80%.  Early success is achieved before all MCI/Prodromal subjects complete 
18 months of treatment and can only be determined after at least 200 MCI/Prodromal
subjects have been randomized.  If early success is declared before full randomization, the 
Page 908 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 17 of 156
randomization of new MCI/Prodromal subjects will stop but subjects already randomized 
into the study will receive the full 18 months of treatment (following confirmation from the 
Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if the 
probability that the ED90 is better than placebo by the clinically significant difference of 25% 
is less than 5% at 18 months of treatment.  The statistical futility boundary is binding; if the 
statistical futility boundary is crossed the study will be considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if an 
ED90 at 18 months treatment has at least an 80% probability of achieving 25% improvement 
over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01): All mild to moderate AD subjects 
will be included in the efficacy evaluations of the Mild to Moderate AD cohort.   The analysis of the 
Mild to Moderate AD cohort is based on the group sequential design.  Interim analyses in the Mild to 
Moderate AD cohort will only be performed after the MCI/Prodromal cohort crosses the early 
success boundary.  The early efficacy signal based on the change from baseline of ADCOMS at 
18 months is defined as crossing the interim-analysis boundaries for overwhelming efficacy in the 
mild to moderate AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets 
alpha spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and final 
analyses, respectively, according to 2 planned interim analyses at the 60% and 80% information 
fraction. (revised per Amendment 01)
Analysis for the primary endpoint 
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the prespecified 
censoring rule applied.  The primary endpoint is the change from baseline to 18 months in the derived 
ADCOMS.  The dose-response of the primary endpoint is modelled with a first-order normal 
dynamic linear model, where Normal and Inverse-Gamma priors are used.  The primary efficacy 
analysis will calculate the Bayesian posterior probability that the dose identified is the most likely 
ED90 dose that achieves 25% improvement over the placebo arm.  At each interim analysis and the 
final analysis, 2 Bayesian probabilities will be summarized for each active dose: the probability it is
the ED90 dose and the probability of achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, CDR, CBB, ISLT, and 
FAQ), subjects will be censored at the time of initiation of treatment with AChEIs or memantine, if 
they were not on these medications at the time of Baseline cognitive assessment (Visit 2), and will be 
censored at the time of dose adjustment of AChEIs or memantine if they were already on stable 
treatment with these medications at the time of Baseline cognitive assessment (Visit 2).  The value of 
the primary endpoint for censored subjects will be imputed using data up to the censoring time and 
Bayesian longitudinal modeling.
Sensitivity analyses of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods described above 
as well as conventional statistical methods.  The following additional Bayesian analyses will be 
conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as primary 
analysis. This is an intent-to-treat analysis without any censoring.  
Page 909 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 18 of 156

In case of early success, the primary analysis as well as the above sensitivity analyses will be 
repeated after all subjects have completed 18 months of treatment or have been lost to 
follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with repeated 
measures (MMRM) on the change from baseline in the derived ADCOMS at 18 months.  The model 
will include treatment groups, randomization stratification variables (the presence or absence of 
ongoing treatment with AChEIs or memantine or both, and ApoE4 status), and baseline ADCOMS as 
covariates.  Other covariates such as adjusted hippocampal volume will be studied.  These analyses 
will be performed as sensitivity analyses on the FAS as well as the per protocol set, and as such, no 
multiplicity adjustments will be made to account for the interim analyses.  In case of early success, 
the conventional analyses will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint:  (revised per Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 18 months in 
mild to moderate AD. If there is no treatment group-by-population interaction in the overall study, 
the MMRM analysis will include all subjects (MCI/Prodromal or mild to moderate AD) in the overall 
study.  Otherwise, the MMRM analysis will only include subjects in the Mild to Moderate AD 
cohort.  The comparison between placebo and active doses will be performed within mild to moderate 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will be used 
to control for multiplicity due to multiple comparisons.
Analysis for exploratory endpoints
(revised per Amendments 01 and 02)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild to 
moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to moderate 
AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal and mild to moderate AD subjects. Data from early discontinuations will 
also be included.  (revised per Amendment 02)

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, CBB, 
and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal and mild
to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 
4 weeks and 18 months of treatment, and during posttreatment follow-up in MCI/Prodromal 
and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12, and 18 months as measured by vMRI in MCI/Prodromal and mild to 
Page 910 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 19 of 156
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months in 
MCI/Prodromal and mild to moderate AD subjects 

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 18 months 
of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between each 
treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship between the 
following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in imaging 
biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 and 18 months in 
MCI/Prodromal and mild to moderate AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to assess the 
effect of ApoE status in this relationship.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma
biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1 will be assessed and 
data will be presented graphically.  Baseline levels and changes in t-tau and p-tau will be correlated 
with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  Summary statistics for CSF 
biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in plasma and CSF 
will be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  Additionally, the relationship between CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between CSF exposure to E2609 and the change
from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  Any emergent relationships will be explored through 
population PK/PD modeling.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, and vital sign measurements will be summarized 
Page 911 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 20 of 156
by treatment group using descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 
[natural killer cells] and CD14 [macrophages]) and regulatory T cells will be summarized in the same 
manner as other laboratory parameters.  Mean lymphocyte subsets and the mean change from 
baseline in lymphocyte subsets will also be displayed graphically over time by dose.  Serum IgG, 
IgM, IgA will be measured and summarized in the same manner as other laboratory parameters.
Interim Analyses
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and 
perform interim analyses of these data.  Investigators, other clinical site staff, subjects and 
caregivers/informants will remain blinded to study treatment.  (revised per Amendment 03)
An interim safety analysis will also be conducted when the first 60 subjects have completed 12 weeks 
of treatment (or discontinue study drug early) in Stage A. (revised per Amendments 01 and 03)
The MCI/Prodromal Cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be conducted 
by an independent committee that has expertise with Bayesian adaptive design in clinical studies.  An 
unblinded external independent analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim analysis 
and response adaptive randomization process through review of efficacy data.  In addition, the 
committee will act in an independent advisory capacity to monitor the Bayesian interim analysis 
outcomes according to the early success and futility boundaries prespecified in the protocol.  The 
committee will not be charged with any subject safety issues; this will remain the responsibility of the 
DSMB.  The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  The study may be stopped for safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal subjects 
have been randomized into the study (ie, including MCI/Prodromal subjects from both Stage A and 
Stage B).  (revised per Amendment 01) Further interim efficacy analyses will be conducted after 
each additional 50 MCI/Prodromal subjects have been randomized, up to a maximum of 
500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 500 subjects 
randomized).  If the study reaches full randomization, additional interim analyses will be conducted 
every 3 months until all subjects complete 18 months of treatment.  The study will be monitored for 
futility at each interim analysis.  Starting at the 200 subjects’ interim analysis, the study will be 
monitored for success at each interim analysis.  Each interim analysis will be conducted on data for 
the derived ADCOMS.  
If the predefined early success criteria are met during the recruitment period, further recruitment and 
enrollment of MCI/Prodromal subjects into the study will stop (following confirmation from the 
Sponsor’s Senior Management) and all currently randomized subjects will complete the full 
18 months of treatment.  No further interim analyses will be conducted after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized into the 
study and the treatment of subjects already randomized into the study will stop and the study will be 
declared as “failed”.  All subjects will be monitored for safety for 3 months following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all subjects 
will complete 18 months of treatment.  Interim efficacy analyses will be conducted every 3 months 
Page 912 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 21 of 156
after full randomization is reached to assess futility and early success until all subjects complete 
18 months of treatment.  After full randomization, all study subjects will stop treatment only in the 
event of futility. 
The Mild to Moderate AD Cohort (revised per Amendment 01)
A group sequential design will be used for the Mild to Moderate AD cohort.  This design includes 
3 looks, 2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the first, 
second, and final analyses, respectively.  If the actual information fraction during the interim analyses 
is different from 60% or 80% at the interim, the efficacy boundaries will be adjusted based on the 
actual information fraction.  If early success in the MCI/Prodromal cohort is not achieved before the 
final analysis that is performed when all subjects have completed 18 months treatment, then only a 
final analysis will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort based on 
the data for mild to moderate AD subjects available at that time.  (revised per Amendment 01)
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses
for the first 100 MCI/Prodromal subjects randomized, including  those randomized from both Stage 
A and Stage B).  Thereafter, randomization probabilities to each treatment group will be updated at 
each interim analysis, such that the randomization probability will be increased for the placebo group 
and dosage groups that represent the potential target dose (ED90), and simultaneously decreased for 
other active arms.  (revised per Amendment 01)
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 dose 
groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to moderate AD 
subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 50 mg E2609) at a 1:1:1 
ratio. (revised per Amendment 01)
Stratification (revised per Amendment 01)
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no). (revised per Amendment 01)
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by means of 
simulations.  Extensive study simulations have shown that a total of 500 subjects will be sufficient to 
demonstrate that the most likely ED90 dose achieves a 25% improvement over placebo with a 
probability of at least 80% in the interim and final analyses.  There is at least a 90% probability of 
study success for the dose response scenarios where treatment was considered to have a clinically 
meaningful treatment effect.  Simulations have also shown that if there is no obvious dose effect, the 
probability of falsely claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects per 
Page 913 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 22 of 156
group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 1 null 
hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s method with 1-sided 
alpha of 0.05.  The statistical power was estimated through simulation for a moderate dose-response 
assumption that the percent reduction in change from baseline of total hippocampal volume compared 
with placebo would be 15%, 20%, and 25% corresponding to the 3 doses, respectively.  The 
estimated power for actual planned study sample size is 78% at 18 months assuming an attrition rate 
of 20% at 18 months.  Under a stronger dose-response assumption (ie, the percent reduction in 
change from baseline of total hippocampal volume compared with placebo is twice as much as that in 
the moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those for 
vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of change from baseline was estimated at 0.33 and a reasonable mean difference between 
treatment and placebo was estimated as 0.25 (standardized uptake value ratio [SUVR]).  Assuming a 
moderate dose-response, the best dose would achieve a difference of 0.25 (SUVR) and the middle 
and low doses would achieve a difference of 0.2 and 0.15 (SUVR), respectively, it would require a 
total of 100 subjects from all 4 arms at 18 months to achieve 80% power.
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per Amendment 01)
ADCOMS at Month 18: The null hypothesis is that there is no difference between active dose and 
placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in the secondary analysis 
section.  The statistical power was estimated through simulation for the dose-response assumption 
that the percent reduction in change from baseline of ADCOMS at 18 months compared with placebo 
would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated power for the 
actual planned 200 mild to moderate AD subjects is approximately 80% assuming a 2-sided alpha of 
0.05. (revised per Amendment 01)
Page 914 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 23 of 156
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................23
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................28
5
ETHICS............................................................................................................................31
5.1
Institutional Review Boards/Independent Ethics Committees ..............................31
5.2
Ethical Conduct of the Study.................................................................................31
5.3
Subject Information and Informed Consent...........................................................32
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................34
7
INTRODUCTION ...........................................................................................................35
7.1
Nonclinical and Clinical Safety Data.....................................................................36
8
STUDY OBJECTIVES....................................................................................................39
8.1
Primary Objectives.................................................................................................39
8.2
Secondary Objectives.............................................................................................39
8.3
Exploratory Objectives ..........................................................................................39
9
INVESTIGATIONAL PLAN..........................................................................................41
9.1
Overall Study Design and Plan..............................................................................41
9.1.1
Prerandomization Phase...............................................................................44
9.1.1.1
Screening Period..................................................................................45
9.1.1.2
Baseline Period ....................................................................................47
9.1.2
Randomization Phase...................................................................................47
9.1.2.1
Treatment Period..................................................................................47
9.1.2.2
Early Discontinuation ..........................................................................48
9.1.2.3
Follow-up Period .................................................................................48
9.2
Discussion of Study Design, Including Choice of Control Groups.......................48
9.2.1
Overview......................................................................................................48
9.2.2
Rationale for Study Population....................................................................49
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................50
9.2.4
Rationale for Clinical Endpoints..................................................................51
9.2.5
Rationale for Biomarkers.............................................................................52
9.2.5.1
Overall Rationale .................................................................................52
9.2.5.2
Soluble Biomarkers in CSF .................................................................52
9.2.5.3
Amyloid PET .......................................................................................53
9.2.5.4
vMRI....................................................................................................53
9.2.6
Clinical Risks and Mitigation Strategy........................................................54
Page 915 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 24 of 156
9.3
Selection of Study Population................................................................................56
9.3.1
Inclusion Criteria .........................................................................................56
9.3.2
Exclusion Criteria ........................................................................................57
9.3.3
Removal of Subjects from Therapy or Assessment.....................................61
9.4
Treatments..............................................................................................................65
9.4.1
Treatments Administered.............................................................................65
9.4.2
Identity of Investigational Product...............................................................65
9.4.2.1
Chemical Name and Formula of E2609...............................................66
9.4.2.2
Comparator Drug .................................................................................66
9.4.2.3
Labeling for Study Drug......................................................................66
9.4.2.4
Storage Conditions...............................................................................66
9.4.3
Method of Assigning Subjects to Treatment Groups...................................67
9.4.4
Selection of Doses in the Study...................................................................67
9.4.5
Selection and Timing of Dose for Each Subject..........................................69
9.4.6
Blinding........................................................................................................69
9.4.7
Prior and Concomitant Therapy...................................................................70
9.4.8
Treatment Compliance.................................................................................71
9.4.9
Drug Supplies and Accountability...............................................................71
9.5
Study Assessments.................................................................................................73
9.5.1
Assessments.................................................................................................73
9.5.1.1
Demography.........................................................................................73
9.5.1.2
Baseline Assessments ..........................................................................73
9.5.1.2.1
Medical History and Physical Examinations.................................73
9.5.1.2.2
Viral Testing ..................................................................................74
9.5.1.2.3
B12 Testing....................................................................................74
9.5.1.2.4
TB Exposure Testing .....................................................................74
9.5.1.2.5
Urine Drug Testing ........................................................................74
9.5.1.3
Efficacy Assessments...........................................................................74
9.5.1.3.1
Psychometric Assessments ............................................................74
9.5.1.3.2
Volumetric MRI.............................................................................76
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................76
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................76
9.5.1.4.1
Pharmacokinetic Assessments .......................................................76
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................77
9.5.1.5
Safety Assessments..............................................................................79
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..79
Page 916 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 25 of 156
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................82
9.5.1.5.3
Laboratory Measurements .............................................................83
9.5.1.5.4
Vital Signs and Weight Measurements..........................................85
9.5.1.5.5
Physical Examinations...................................................................85
9.5.1.5.6
Electrocardiograms ........................................................................85
9.5.1.5.7
Safety MRI.....................................................................................86
9.5.1.5.8
Dermatological Assessment...........................................................87
9.5.1.5.9
Neurological Examination .............................................................87
9.5.1.5.10
Pregnancy Test...............................................................................87
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................88
9.5.1.5.12
Biomarker Samples........................................................................88
9.5.1.5.13
Ophthalmic Examinations..............................................................88
9.5.2
Schedule of Procedures/Assessments ..........................................................88
9.5.2.1
Schedule of Procedures/Assessments ..................................................88
9.5.2.2
Description of Procedures/Assessments Schedule...............................97
9.5.3
Appropriateness of Measurements...............................................................98
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................98
9.5.4.1
Reporting of Serious Adverse Events..................................................98
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................99
9.5.4.3
Reporting of Events Associated with Special Situations.....................99
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................99
9.5.4.3.2
Reporting of Study-Specific Events.............................................100
9.5.4.4
Expedited Reporting ..........................................................................100
9.5.4.5
Breaking the Blind.............................................................................100
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................101
9.5.5
Completion/Discontinuation of Subjects...................................................101
9.5.6
Abuse or Diversion of Study Drug ............................................................102
9.5.7
Confirmation of Medical Care by Another Physician ...............................102
9.6
Data Quality Assurance .......................................................................................102
9.6.1
Data Collection ..........................................................................................102
9.6.2
Clinical Data Management ........................................................................103
9.7
Statistical Methods...............................................................................................103
9.7.1
Statistical and Analytical Plans..................................................................103
9.7.1.1
Study Endpoints.................................................................................103
Page 917 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 26 of 156
9.7.1.1.1
Primary Endpoint.........................................................................103
9.7.1.1.2
Secondary Endpoints ...................................................................103
9.7.1.1.3
Exploratory Endpoints .................................................................104
9.7.1.2
Definitions of Analysis Sets...............................................................104
9.7.1.3
Subject Disposition............................................................................105
9.7.1.4
Demographic and Other Baseline Characteristics .............................105
9.7.1.5
Prior and Concomitant Therapy.........................................................106
9.7.1.6
Efficacy Analyses ..............................................................................106
9.7.1.6.1
Primary Efficacy Analysis...........................................................107
9.7.1.6.2
Secondary Efficacy Analyses ......................................................108
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................109
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................110
9.7.1.7.1
Pharmacokinetic Analyses...........................................................110
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................110
9.7.1.8
Safety Analyses..................................................................................111
9.7.1.8.1
Extent of Exposure.......................................................................111
9.7.1.8.2
Adverse Events ............................................................................111
9.7.1.8.3
Laboratory Values........................................................................112
9.7.1.8.4
Vital Signs....................................................................................113
9.7.1.8.5
Electrocardiograms ......................................................................113
9.7.1.8.6
Other Safety Analyses..................................................................114
9.7.2
Determination of Sample Size ...................................................................114
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................114
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort 
(revised per Amendment 01) .............................................................115
9.7.3
Interim Analysis.........................................................................................115
9.7.4
Other Statistical/Analytical Issues .............................................................117
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................118
10
REFERENCE LIST .......................................................................................................119
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....123
11.1
Changes to the Protocol .......................................................................................123
11.2
Adherence to the Protocol....................................................................................123
11.3
Monitoring Procedures.........................................................................................123
11.4
Recording of Data................................................................................................124
11.5
Identification of Source Data...............................................................................124
11.6
Retention of Records............................................................................................125
Page 918 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 27 of 156
11.7
Auditing Procedures and Inspection....................................................................125
11.8
Handling of Study Drug.......................................................................................125
11.9
Publication of Results ..........................................................................................126
11.10 Disclosure and Confidentiality ............................................................................126
11.11 Discontinuation of Study .....................................................................................126
11.12 Subject Insurance and Indemnity.........................................................................127
12
APPENDICES ...............................................................................................................128
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................63
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................64
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................68
Table 4
Clinical Laboratory Tests...........................................................................83
Table 5
Lymphocyte Subtyping..............................................................................85
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................89
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................92
Table 8
Summary of Blood and CSF Sample Volumes..........................................97
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202............................................................42
Figure 2
Assessments to be Performed at Screening by Tier...................................46
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................128
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........131
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 145
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................148
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................151
Page 919 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 28 of 156
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg 1-
42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carobxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
ECG
electrocardiogram
Page 920 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 29 of 156
Abbreviation
Term
eCRF
electronic case report form
ED
early discontinuation
ED90
lowest effective dose that achieves 90% of the greatest treatment effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
Page 921 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 30 of 156
Abbreviation
Term
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OF
O’Brien-Fleming 
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 922 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 31 of 156
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR)
regarding clinical studies, including Part 50 and Part 56 concerning informed subject 
consent and IRB regulations and applicable sections of US 21 CFR Part 312
Page 923 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 32 of 156

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for 
studies conducted within any European Union country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 924 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 33 of 156
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for 4 weeks and 18 months (or at Early 
Discontinuation).  This consent for CSF sample collection is not required for study eligibility. 
(revised per Amendment 02)
Page 925 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 34 of 156
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 125 investigational sites globally (40 sites in the United States for 
Stage A and 125 sites globally for Stage B). (revised per Amendments 01 and 02)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 926 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 35 of 156
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010, Lu, et 
al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, thus 
accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild to moderate dementia due to Alzheimer’s Disease (referred to as mild to moderate AD
throughout the protocol) to determine whether the effects of E2609 in this later stage 
population are comparable with those established in the MCI/Prodromal population within 
Page 927 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 36 of 156
this same study. (revised per Amendment 01)  In the MCI/Prodromal population, Bayesian 
response adaptive randomization design is used with frequent interim analyses to continually 
update randomization allocation based on emerging clinical endpoint data.  This approach 
allows for ongoing assessment of drug futility or evidence of early success and can mitigate 
the risks associated with larger and longer studies required to demonstrate clinical efficacy 
by leading to more efficient study termination or early advancement to a Phase 3 program.  
Results from this study will guide both the decision to move into Phase 3 development and 
the selection of the dose strengths to be taken into Phase 3.  Moreover, this study is intended 
to be supportive for registration in the MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5, 15, and 50 mg) administered once daily (QD) for 18 months.  In the mild to moderate AD 
population, this study will compare placebo and 2 oral doses of E2609 (15 and 50 mg) 
administered QD for 18 months.  To date, the longest duration of dosing with E2609 is 
14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  (revised per 
Amendment 01)  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the first 60 randomized subjects have completed 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  The study also includes a 
number of exclusion criteria, specific blinded safety monitoring procedures and safety 
criteria for discontinuation of study drug in light of the preclinical and clinical safety data 
collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Page 928 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 37 of 156
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the pharmacokinetic (PK) levels of E2609 and the 
pharmacodynamic (PD) effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
Page 929 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 38 of 156
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 930 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 39 of 156
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendment 02)
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild to moderate AD subjects (revised per Amendment 01)  
8.3
Exploratory Objectives
(revised per Amendments 01 and 02)  
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after 4 weeks and 18 months of treatment in MCI/Prodromal and mild to moderate AD 
subjects (revised per Amendment 02)
Page 931 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 40 of 156
4. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, in 
MCI/Prodromal and mild to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b. The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d. The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
5. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
posttreatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
6. To characterize the population PK of E2609 in MCI/Prodromal and mild to moderate AD 
subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild to moderate AD subjects
Page 932 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 41 of 156
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study 202 is a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per Amendment 
01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) before expanding enrollment to include a larger number of subjects in Stage B.  
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective 
of whether they were recruited into Stage A or Stage B.  Bayesian response adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B.  All mild to 
moderate AD subjects will be included in the efficacy evaluation of that cohort. (revised per 
Amendment 01)  
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
In Stage A, all subjects (MCI/Prodromal and mild to moderate AD) will be randomized 
1:1:1:1 to 4 treatment groups (E2609 at 3 doses or placebo).  In Stage B, randomization of 
MCI/Prodromal subjects will start off at a 1:1:1:1 ratio (E2609 at 3 doses or placebo), until a 
total of 100 MCI/Prodromal subjects have been randomized.  Remaining subjects in the 
MCI/Prodromal cohort will be randomized according to response adaptive randomizations 
based on the ADCOMS results using the Bayesian interim efficacy analyses.  Subjects with 
mild to moderate AD who are recruited in Stage B will be randomized in a 1:1:1 ratio to 
3 treatment groups (E2609 at 2 doses or placebo). (revised per Amendment 01)  
Page 933 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 42 of 156
An overview of the study design is presented in Figure 1 .
Figure 1
Design of Study E2609-G000-202
(revised per Amendments 01 and 02 )
R = randomization.
Stage A
Stage A will be limited to approximately 40 sites in the United States.  (revised per 
Amendments 01 and 02) Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 
4 treatment groups within each clinical cohort.  (revised per Amendment 01)  There will be 
no Bayesian adaptation during Stage A.  In addition to the placebo group, 3 doses of E2609
will be used to reduce CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 
75% (50 mg) from baseline, respectively, at steady state.  PK/PD modeling shows these
doses should achieve these targets when administered QD with food and will be evaluated
based on the 4-week assessment of CSF Aβ(1-x) from subjects who provide voluntary
consent for CSF measurement. (revised per Amendment 02) (see Section 9.4.4).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A, an independent DSMB (including at least 1 immunologist) will review all safety 
data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
Page 934 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 43 of 156
review as to whether any change(s) to the study are necessary.  Unless the DSMB 
recommends otherwise, randomization of subjects into Stage A will continue until 
60 subjects have been randomized and dosed.  (revised per Amendment 01)  
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who consent 
to provide CSF samples at Baseline and after 4 weeks of study drug.  These interim analyses, 
as well as analyses of safety data, will be performed on an ongoing basis throughout Stage A.  
Refer to Section 9.7.3 for more detail.  (revised per Amendment 03)  These data will be used 
to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions from 
baseline in CSF Aβ(1-x) levels (see Section 9.4.4).  (revised per Amendments 01 and 02)  
The mean percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks of 
treatment for each dose of E2609 and its 90% confidence interval will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data from Stage A and will relate the average steady state plasma 
concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline after 
4 weeks of dosing.  (revised per Amendment 02)
Once 60 subjects in Stage A have completed at least 12 weeks of treatment (or discontinued 
study drug early) an interim safety analysis will be conducted by Eisai and the DSMB.  
(revised per Amendment 01)  Subjects in Stage A will continue study drug while the DSMB 
reviews all the available safety data, but randomization of additional subjects will not take 
place (ie, recruitment into Stage B will not commence) until the safety analysis is completed 
by the DSMB.  At the time of this interim safety analysis, some subjects will have more than 
12 weeks of safety data.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol. Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  
(revised per Amendment 02) Based on data from Stage A, the protocol will be reviewed and 
may be amended before beginning Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment in the study is 
completed; following this the DSMB will meet approximately every 6 months.
Stage B will be conducted globally and will enroll, randomize, and dose additional eligible 
subjects up to a maximum of 500 MCI/Prodromal subjects and up to a maximum of 200 mild 
to moderate AD subjects. The final total number of MCI/Prodromal subjects will depend 
upon whether the prespecified criteria for either early success or futility are met.  (revised per 
Amendment 01)  
Page 935 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 44 of 156
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5, 15, and 50 mg QD), whereas the Mild to Moderate AD 
cohort will only include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)  
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according 
to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  
(revised per Amendment 01)  The remaining subjects in the MCI/Prodromal cohort in Stage 
B will then be randomized according to response adaptive randomizations based on the 
ADCOMS results using the Bayesian interim efficacy analyses.  The mild to moderate AD 
subjects will be randomized according to a fixed schedule (1:1:1 placebo; 15 mg E2609; 
50 mg E2609) throughout Stage B. (revised per Amendment 01)  
Interim analyses are planned and are discussed in Section 9.7.3. (revised per Amendment 
03)  
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization the clinician will provide a judgment on the classification of a subject as either 
MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This judgment
may be discussed and reviewed with the Sponsor or Sponsor’s representative, as necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per 
Amendment 02)
Page 936 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 45 of 156
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Page 937 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 46 of 156
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it 
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 938 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 47 of 156
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination will be 
performed.  A urine pregnancy test will be conducted for females of childbearing potential.  
Blood will be collected from all subjects for clinical chemistry and hematology, lymphocyte 
subset analyses, Ig analyses, and PD assessments.  Blood samples will be collected and 
stored for determination of a subject’s previous exposure to infective pathogens in the event 
of AEs that warrant further investigation occurring at a later point in the study.  Psychometric 
assessments will be administered to the subject in the order stated in Table 6.  The caregiver 
or informant needs to be present at this visit.  The Columbia Suicide Severity Rating Scale 
(C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, CSF will be obtained at this visit for PK 
and PD assessments (see Section 9.5.1.5.3).  (revised per Amendment 02)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Page 939 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 48 of 156
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
9.1.2.3
Follow-up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Oct 2019 (end date will 
depend on actual recruitment rate).

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The 2 stage design of the study allows for the safety and tolerability of E2609 to be assessed 
in a limited number of subjects (n=60) before expanding recruitment into a larger population 
of subjects. (revised per Amendment 01)  
Page 940 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 49 of 156
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild to 
moderate AD to determine whether the effects of E2609 in this later stage population are 
comparable with those established in the MCI/Prodromal population within this same study 
(see Section 9.2.3 for discussion of the Bayesian design used in this study). (revised per 
Amendment 01)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of 
well-established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (see Section 9.2.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; and a cognitive 
and functional assessment, which is the change from baseline in the derived ADCOMS at 
18 months of treatment in mild to moderate AD subjects.  (revised per Amendments 01 and 
02)  Exploratory endpoints including assessments of efficacy, safety and other biomarkers
are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
Page 941 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 50 of 156
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 
2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild to moderate AD will be assessed as a “nested” population that does not 
follow the Bayesian adaptive design.  It was not considered appropriate to have a Bayesian 
design for both cohorts as this would have substantially increased the overall study sample 
size, delayed analyses of dose response, and would have added background “noise” for the 
Page 942 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 51 of 156
comparison of subjects with MCI/Prodromal AD compared with those with mild to moderate 
AD. Data from each cohort will be analyzed independently for the purposes of decision 
making.  A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild 
to moderate AD confounding the results for the primary population (MCI/prodromal).  
(revised per Amendment 01)  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
Page 943 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 52 of 156
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility 
inclusion criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
Page 944 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 53 of 156
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both total tau (t-tau) and p-tau are sensitive markers of axonal and neuronal degeneration 
(t-tau) and neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel 
with disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have 
been correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful 
predictors of cognitive decline and progression to dementia due to AD.  Rebalancing 
dysregulated amyloid production early in the process may positively affect the 
neurodegenerative process and thus affect these markers and benefit the disease trajectory.  
Therefore, monitoring these markers in conjunction with amyloid imaging may provide 
further supportive evidence of efficacy.  
Baseline levels of Aβ(1-42), tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted on subjects with Screening PET scans performed for this study (ie, 
historical scans cannot be used for the longitudinal analyses) and will only be conducted until
18-month PET scans of acceptable quality have been obtained for at least 25 subjects per 
treatment arm for each amyloid PET ligand used.  (Revised per Amendment 02)
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
Page 945 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 54 of 156
regions during the early stages of disease and progresses towards the anterior regions of the 
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Two-stage study design:  there will be a pause in recruitment after 60 subjects have
been randomized to study drug (Stage A).  Only after the safety of E2609 in these 
first 60 subjects (consisting of up to 12 weeks data for the later subjects and longer 
dosing periods for the earlier subjects) has been reviewed by the DSMB and 
considered acceptable, will randomization of further subjects into the study 
commence (Stage B). (revised per Amendment 01)

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals
Page 946 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 55 of 156

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and 
percentage change from baseline), skin rash, reoccurrence of herpes virus infections 
including any oral herpes, genital herpes or shingles, other infections, MRI changes, 
ECGs, and pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course 
of the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of
vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will 
be questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and posttreatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood and DNA samples will be taken and stored for all 
subjects, and CSF samples will be taken and stored for all subjects who consent to 
CSF sample collection (revised per Amendment 02).  These samples may be tested in 
the event that a subject develops AEs that warrant further investigation (eg, if a 
subject develops a treatment-emergent infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals
during the Treatment Period, and at the final Follow-Up Visit.

Full neurological examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  Details of the neurological 
examination are given in Section 9.5.1.5.9.
Page 947 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 56 of 156

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using 
the detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, 
Baseline, and at regular intervals during the Treatment and Follow-Up Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 2 off-treatment Follow-Up
visits (4 and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated.

An ophthalmic examination will be conducted at Baseline and if the subject 
experiences visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will randomize 60 eligible MCI/Prodromal or mild to moderate AD subjects at 
approximately 40 sites in the United States (revised per Amendment 02).  There will be no 
restriction to the number of subjects from either population.  Stage B will randomize subjects
at approximately 125 sites globally.  Recruitment will continue in Stage B until a maximum 
of approximately 500 MCI/Prodromal subjects and up to a maximum of approximately 200 
mild to moderate AD subjects have been randomized (including subjects randomized during 
Stage A).  The final total number of MCI/prodromal subjects will depend upon whether the 
prespecified criteria for either early success or futility are met.  The number of mild to 
moderate AD subjects randomized in Stage B will depend upon the number of mild to 
moderate AD subjects randomized during Stage A. (revised per Amendment 01)
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Required at Screening Visit 1:  
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT. Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
Page 948 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 57 of 156
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitor (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
Page 949 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 58 of 156
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and <1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors 
(eg, meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
Page 950 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 59 of 156
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded. 
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
Page 951 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 60 of 156
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
Page 952 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 61 of 156
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 28 days after study drug discontinuation.
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 4 and 12 weeks after the last dose of study drug (see Section 9.1.2.3).  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie, at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
Page 953 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 62 of 156
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test will be 
discontinued from study drug.
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendment 02)  
Subjects with a >33% reduction from baseline in CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts will also have lymphocyte subset counts 
performed on a weekly basis.  During the early stages of the treatment period, where 
visits are conducted weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already 
scheduled to be measured on a weekly basis and so additional visits or blood draws are 
not required.  (revised per Amendment 02)  For these subjects, the decision as to whether 
the subject remains on study drug or is to be discontinued from study drug will be based 
upon clinical judgment and will take into account any clinical presentation in addition to 
the lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Page 954 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 63 of 156
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue or 
discontinue
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
discontinuation threshold
Retest within 1 week along with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
discontinue study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold or >33% reduction from baseline in CD4 
(T helper cells), CD8 (cytotoxic T cells), or CD19 
(B cells) absolute counts
Lymphocyte subset counts (and 
CBC with differentials) to be 
performed weekly until 
lymphocyte subset counts return 
to ≥ population-adjusted LLN 
or no more than 33% reduction 
from baseline
Decision will be based upon 
lymphocyte subset counts and 
clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  (table revised per Amendment 02)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds or have shown >33% reduction from baseline, subjects with 
infections of moderate intensity will be discontinued from study drug (eg, subjects whose 
infections are not localized, or subjects who are systemically unwell, or who require 
systemic anti-infective drug treatment).  All subjects with infection who are discontinued 
from study drug will be followed for a period of 12 weeks or until the infection resolves/
stabilizes or until the CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) 
absolute counts have returned to greater than population-adjusted LLN (whichever comes 
latest). (revised per Amendment 02)
Page 955 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 64 of 156
Table 2
Study Drug Actions for Lymphocyte Subset 
Absolute Counts and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
below discontinuation threshold
If confirmed 
with repeat 
testing within 
1 week, then 
discontinue
study drug.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
between population-adjusted LLN and 
discontinuation threshold or >33% 
reduction from baseline in CD4 (T helper 
cells), CD8 (cytotoxic T cells), or CD19 
(B cells) absolute counts
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
always > population-adjusted LLN and no 
reduction from baseline >33%
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug unless 
discontinuation is 
clinically indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  Table revised per Amendment 02
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 4 and 12 weeks after the last dose of 
study drug.  They will also undertake an Unscheduled Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
be performed at approximately the time of the second Follow-Up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
Page 956 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 65 of 156
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered in Stage A and Stage B are shown below and in Figure 1.
The 2 highest E2609 doses (15 and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A, will be used for the mild to moderate AD population in Stage B.
(revised per Amendment 01)  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo.
(revised per Amendment 01)  
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5, 15, 50 mg, or placebo.  The tablets 
Page 957 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 66 of 156
will be supplied by the Sponsor in labeled blister packs.  The product release certificates for 
E2609 and placebo will be included in the clinical study report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-
4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
Page 958 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 67 of 156
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for Stage A (all subjects), for Stage B MCI/Prodromal subjects and Stage B for mild to 
moderate AD subjects are described in Section 9.4.1. (revised per Amendment 01)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Page 959 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 68 of 156
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1
Activity
% Reduction 
CSF A(1-x)
5
6.2
3.3
80.3
16.2
33
15
18.6
10
240.9
36.6
56
50
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = Beta-amyloid converting enzyme, CSF = cerebrospinal fluid,  Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients. (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 400 mg (17.3% 
decrease).  No subjects had infections or drug rash while receiving E2609 100 mg QD or at 
lower doses in Study 002, whereas at 200 and 400 mg QD, 4 subjects had symptomatic 
orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The highest dose 
for Study 202 of 50 mg QD (tablet administered with food) is therefore expected to have a 
similar or better safety profile compared with the 100 mg QD capsule (administered fasted) 
in Study 002.  Specific exclusion criteria, blinded and unblinded safety monitoring 
procedures, and safety criteria for discontinuation from study drug are included in this study
in order to mitigate any immunology-related risk with E2609, particularly in light of the 
progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
In Stage A, all subjects will be randomized to receive either placebo or E2609 at 5, 15, or 
50 mg QD.  In Stage B, subjects in the MCI/Prodromal cohort will continue to be 
randomized to receive either placebo or E2609 at 5, 15, or 50 mg QD. In Stage B, subjects in 
the Mild to Moderate AD cohort will be randomized to receive either placebo or E2609 at 
15 or 50 mg QD, but not the 5-mg QD dose.  The rationale for not including an E2609 5-mg 
QD dose in the dose regimens for Stage B subjects with mild to moderate AD is that more 
Page 960 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 69 of 156
advanced disease may require greater reduction in CSF Aβ levels for comparable effects. 
(revised per Amendment 01)  
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who have 
provided CSF samples at Baseline and after 4 weeks of study drug.  These data will be used 
to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions from 
baseline in CSF Aβ(1-x) levels.  (revised per Amendments 01 and 02)  The mean percentage 
change from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of 
E2609 and its 90% confidence interval will be derived.
In addition, exploratory PK/PD 
modeling will be conducted. This PK/PD modeling will use the observed PK and PD data 
from Stage A and will relate the average steady state plasma concentration of E2609 to 
steady state CSF Aβ(1-x) percentage reduction from baseline after 4 weeks of dosing.
(revised per Amendment 02)
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects, caregivers/informants, and 
all clinical site personnel involved with the conduct and interpretation of the study, including 
investigators will be blinded to the treatment codes (double-blind).  In order to make 
decisions about the remainder of the study as well as the full E2609 clinical development 
program, the sponsor will unblind safety, PK, and PD data on an ongoing basis and perform 
interim analyses of these data.  (revised per Amendment 03)
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
Page 961 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 70 of 156
The PK/PD interim analysis to evaluate the E2609 doses to be used for Stage B will be 
conducted by an independent group (revised per Amendment 02).  Any changes to dose will 
be reflected in an amendment to the protocol and the Statistical Analysis Plan will detail how 
data will be handled in the primary analysis.  
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and
Listing 6.  Medications that are permitted with restrictions are listed in Listing 7, Listing 8, 
and Listing 9.
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives 
or 7 days (whichever is longer) before randomization 

Drugs which may cause QTc prolongation are not permitted for a period of 
5 half-lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Page 962 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 71 of 156
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not 
permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
Page 963 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 72 of 156

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of 
the principal investigator’s current medical license (required for United States sites) 
or medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, and (e) 
documentation of returns to the sponsor.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs
and empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and, together with unused study drugs that were shipped to the site 
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
Page 964 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 73 of 156
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
Page 965 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 74 of 156
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  At the Screening Visit, the recommended order of 
assessments is: MMSE, ISLT (immediate recall), CBB, ISLT (delayed recall), CBB (repeat 
CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the 
assessments are to be conducted in the following order: MMSE, CDR, ADAS-cog14, FAQ,
ISLT (immediate recall), CBB, and ISLT (delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild to moderate AD.  (revised per Amendment 01)  
Page 966 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 75 of 156
It also shows sensitivity to treatment effects with AChEIs.  The ADCOMS assesses both 
cognitive and functional domains and can be offered as a single primary clinical endpoint.  
The ADCOMS has a range from 0 to 1.97.  
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test where the subject presses a key when the card 
is turned face up from a pack of cards (“Has the card turned over”).  Speed of 
response is the measure.
2. Identification – a simple choice reaction time test where the subject presses 1 of 
2 keys when the card just turned face up is either a red card or a black card (“Is the 
card red”).  Speed of response is the measure.
3. One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial 
or not (“Is the previous card the same”).  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not 
in the task (“Have you seen this card before in this task”).  Accuracy of response is 
the measure.
ISLT: The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects are read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Mini Mental State Examination: A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:
The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire:
Either a caregiver or informant or the subject 
provides performance ratings (from 0 to 3) on 10 complex activities of daily living performed 
within the preceding 4 weeks.  Scores range from 0 (independent) to 30 (dependent).  
Page 967 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 76 of 156
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of E2609.  For 
subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of E2609 concentrations. 
(revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with E2609.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Page 968 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 77 of 156
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A second PK blood sample will be collected as close as possible in time to 
the LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the first report of an SAE or severe unexpected 
AE and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed between 4 and 
8 hours postdose and at a similar time of day (±1 hour) for each individual subject.  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE.  The plasma sample will be used for 
Aβ(1-x) analysis and may be used for exploratory biomarker analyses (eg, miRNA).  Aβ(1-x) 
in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF Aβ(1-42), 
t-tau, and p tau will be performed using ELISAs.  BACE1 levels will be measured using 
internally developed fluorescence resonance energy transfer and ELISA based assay(s).  
Substrates of BACE1 inhibition may also be explored using Western blots or other amenable 
methodology if clinical observations warrant and if analytes can be reliably tested in samples 
collected.
Page 969 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 78 of 156
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops treatment-
emergent AEs that warrant further investigation (eg, treatment-emergent infection).  For 
subjects who consent to CSF sample collection, CSF samples from the Baseline Visit will 
also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, but 
not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, or 
human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of treatment (or at ED, providing the subject has received at least 
39 weeks of study drug).  Longitudinal amyloid PET imaging will only be conducted on 
Page 970 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 79 of 156
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses) and will only be conducted until acceptable 18-month
PET scans have been obtained for at least 25 subjects per treatment arm for each amyloid 
PET ligand used (Table 6).  (revised per Amendment 02)  PET scanning will be performed 
with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and posttreatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not 
necessary to report every sign or symptom as a separate AE if the overall disease 
[diagnosis] is being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline)
Page 971 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 80 of 156

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, discontinuation of study 
drug, or withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  For subjects 
who discontinue early from study drug but undertake further efficacy assessments, AEs will 
only be collected for 3 months after the last dose of study drug, ie, through to the second 
follow-up visit (Visit 20).  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
collected for 3 months after the last dose of study drug, ie, through to the second follow-up 
visit (Visit 20).  For subjects who discontinue early from study drug but continue with further 
efficacy assessments, SAEs will be solicited only for 3 months after the last dose of study 
drug, i.e. up to the 2nd follow up visit (Visit 20). However, any SAEs volunteered by 
subjects after this time point must be reported according to standard procedures.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADCOMS, ADAS-cog14, MMSE, and CBB 
(see Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment 
Period, and if this cognitive decline is considered by the investigator to be excessive relative 
to the subject’s recent AD history, this finding should be reported as an AE.
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 
Page 972 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 81 of 156

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following adverse events will require the collection of information sufficient to provide a 
detailed description of the event, treatment and outcome to the Medical Monitor for the 
study: any treatment-emergent significant laboratory abnormality; any seizures, herpes zoster 
infection, severe infection; any moderate to severe drug rash or any rash lasting more than 
72 hours (regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the second follow-up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Page 973 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 82 of 156
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of 
the event

The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
Page 974 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 83 of 156
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening and Baseline only)  (revised per Amendment 02)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Page 975 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 84 of 156
Table 4
Clinical Laboratory Tests
Category
Parameters
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte subset analyses (see Table 5).  Regulatory T cells will be measured using 
CD4, CD25, and FoxP3 intracellular marker.  
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HBsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials, must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (CD3, CD4, CD8, CD45, CD19, CD16, CD56, and CD14) 
and total lymphocyte counts will be measured in order to provide the lymphocyte subset data 
as shown in Table 5.  In addition, Regulatory T cells will be measured using CD4, CD25, and 
FoxP3 intracellular marker.  Current sponsor data supports the literature showing there is an
age-related decline in lymphocyte subsets (see Appendix 5). These data have been used to 
revise the LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) 
absolute counts to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively)
(revised per Amendment 02).  
Page 976 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 85 of 156
Table 5
Lymphocyte Subtyping 
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
in the supine position for at least 5 minutes.
Page 977 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 86 of 156
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2* Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, and 18 and at the second Follow-Up Visit 
(Visit 20).  In the event of an Unscheduled Visit, the investigator in consultation with the 
sponsor will determine whether or not a safety MRI should be conducted.  If an ED Visit 
takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and Follow-Up Visits at 4 weeks and 12 weeks 
after the last dose of treatment.  Subjects will also undertake an Unscheduled Visit (with 
MRI) at approximately 30 days after the visit at which such MRI features were first 
Page 978 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 87 of 156
identified.  Additional visits may be arranged if clinically indicated in the opinion of the 
investigator, and may occur later than 12 weeks after the final dose of study drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve.  Treatment-emergent abnormal neurological 
findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 979 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 88 of 156
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 980 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 89 of 156
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/ Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary) 
X
X
Demographics
X (Tier 1)
Medical historya
X (Tier 1)
Prior / concomitant medicationsb
X (Tier 1)
X
Vital signs including weightc 
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTd
X (Tier 1)
X
MMSEd
X (Tier 1)
X
CDRd
X (Tier 1)
X
FAQd
X (Tier 1)
X
ADAS-cog14d
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGe
X (Tier 2)
X
Blood and urine for clinical laboratory testsf
X (Tier 2)
X
Blood for lymphocyte subset analysesg
X (Tier 2)
X
Blood for Ig analysesh
X (Tier 2)
X
Blood for viral screeni
X (Tier 2)
Blood for thyroid function testsj
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIk
X (Tier 3)
Amyloid PET scanl
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagem
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
Table revised per Amendment 02
Page 981 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 90 of 156
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization 
can be extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety 
laboratory tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
b:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
c:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
d:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At 
the Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times 
if required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
e:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
f:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
g:
Lymphocyte subsets to be measured include CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), 
CD16/CD56 (natural killer cells) and CD14 (macrophages).  Regulatory T cells will also be measured (CD4, CD25,
FoxP3).  Viability staining may also be employed.  Whenever unscheduled lymphocyte subset tests are performed or 
whenever scheduled lymphocyte subsets are repeated, a CBC with differentials, must also be repeated.  (revised per 
Amendment 02)
h:
Igs to be analyzed include IgG, IgA and IgM.
i:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
j:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine and free thyroxine.
k:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
Page 982 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 91 of 156
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
assessments in the same imaging session. (revised per Amendment 01)
l:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the 
previous 12 months and provided that the scan and result are considered acceptable by the central PET reading group.  
(revised per Amendment 02)
m:
For subjects who consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or at least 
2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be encouraged to 
stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed at a similar time of day (±1 hour) for each 
individual subject. If the LP and cognitive tests are performed on the same day, the LP must be performed after the 
cognitive tests have been completed and the subject should rest and drink some fluid to hydrate before the LP.  The 
CSF sample will be used for PK and PD assessments.  A CSF sample will also be stored for testing in the event that 
the subject develops treatment-emergent adverse events that warrant further investigation (eg, treatment-emergent 
infection). (revised per Amendments 01 and 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops treatment-emergent adverse events that 
warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether 
the subject already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurological examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 983 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 92 of 156
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological assessment via 
photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for lymphocyte subset
analysesl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for Igsm
X
X
X
X
X
X
X
X
X
X
Blood samples for isolation of PBMCs 
X
X
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample for storage for immune statuso
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 984 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 93 of 156
Table 7 Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and exploratory 
biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 985 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 94 of 156
Notes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled.
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20, respectively).  Subjects who discontinue study drug prematurely will also be 
scheduled to return to the study site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these visits have 
not already been performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB, and ISLT) will be conducted.   Regularly scheduled 
clinical efficacy visits do not need to be attended if they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days of either of the Follow-Up 
Visits (Visit 19 and Visit 20).  Subjects who discontinue early from study drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 2 posttreatment Follow-Up visits; 
one 4 weeks after the last dose of study drug and a second 12 weeks after the last dose of study drug (Visit 19 and Visit 20 respectively).  If clinically indicated, more frequent 
safety assessments can be made as UNS assessments or visits during the posttreatment Follow-Up period.  
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at Visit 19.  (revised per Amendment 02)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets to be measured include CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and total 
Page 986 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 95 of 156
lymphocytes.  Regulatory T cells will also be measured (CD4, CD25, and FoxP3). Viability staining may also be employed.  Whenever unscheduled lymphocyte subset tests 
are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be performed. (revised per Amendment 02)
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors. 
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within the 
7 days before Visits 14, 16, and 18 and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will be 
collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14 and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  All visits at which CSF samples are scheduled to be taken also include blood PK and PD assessments and so the subject 
will be dosed at the clinic on these days. A CSF sample will be collected by LP between 4 and 8 hours postdose and at the same time of day as the subject's Baseline LP 
(±1 hour).  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  If 
the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been completed and the subject should rest and drink 
some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical observation.  The CSF sample will not be taken at the 
ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the 
Page 987 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 96 of 156
CSF sample will still be collected unless it was already collected within the past 3 months. (revised per Amendments 01and 02)
w:
Subjects reporting adverse events relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 988 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 97 of 156
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.1.1.1, and Figure 2.
See Section 9.5.1 for a full description of the procedures and assessments to be performed 
during this study.
Table 8
presents the number of blood and CSF samples, and the total volume of blood 
and CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline 
Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
18
2 x 5 mL
16 x 5 mL
90 mL
Lymphocyte subset analyses
18
2 x 4 mL
16 x 4 mL
72 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
9
2 x 2 mL
7 x 2 mL
18 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
322  mL
402  mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 989 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 98 of 156
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the second follow-up visit (Visit 20).  In subjects who 
discontinue study drug early, but continue with efficacy assessments, SAEs only need to be 
solicited up to 3 months after the last dose of study drug.  However, any SAEs volunteered 
by subjects after this time point must be reported according to standard procedures.  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.
Page 990 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 99 of 156
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Page 991 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 100 of 156
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
Page 992 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 101 of 156
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 4 and 12 weeks after the last dose of study drug 
(Visit 19 and Visit 20, respectively) (see Section 9.1.2.3).  See Table 7 for full details of the 
assessments to be performed at these visits.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when 
clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18, if 
these visits have not already been performed).  At these visits, only clinical efficacy 
assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  
Subjects who discontinue early from study drug are considered on study as long as they 
return for their regularly scheduled clinical efficacy visits as outlined above. Subjects who 
discontinue study drug early (as opposed to subjects whose dosing with study drug is 
temporarily suspended under Medical Monitor guidance) will not be permitted to restart 
study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
Page 993 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 102 of 156
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
Page 994 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 103 of 156
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects
(revised per Amendment 01)  
Page 995 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 104 of 156
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01 and 02)  
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD 
subjects as measured by vMRI

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild to moderate AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal and 
mild moderate AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by 
vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal 
and mild to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD 
subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol.  The PP Analysis Set will be used to conduct a 
sensitivity analysis of the primary efficacy endpoint.  Details of the evaluability 
criteria will be determined before database lock and treatment unblinding, and will be 
specified in the statistical analysis plan.
Page 996 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 105 of 156

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement 
and at least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
Page 997 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 106 of 156
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
WHO DD preferred term.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be defined as medications 
that (1) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (2) started on or after the date of the first dose of study drug up to the
date of the last dose.  All medications will be presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy Analyses
The MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  
Page 998 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 107 of 156

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 
25% improvement over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
All mild to moderate AD subjects will be included in the efficacy evaluations of the Mild to 
Moderate AD cohort.  The analysis of the Mild to Moderate AD cohort is based on the group 
sequential design.  Interim analyses in the Mild to Moderate AD cohort will only be 
performed after the MCI/Prodromal cohort crosses the early success boundary.  The early 
efficacy signal based on the change from baseline of ADCOMS at 18 months is defined as 
crossing the interim-analysis boundaries for overwhelming efficacy in the mild to moderate 
AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha 
spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and 
final analyses, respectively, according to 2 planned interim analyses at the 60% and 
80% information fraction. (revised per Amendment 01)  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Page 999 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 108 of 156
Sensitivity analysis of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the PP set and as such, no multiplicity adjustments will be 
made to account for the interim analyses.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint:  (revised per 
Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild to moderate AD.  If there is no treatment group-by-population interaction 
in the overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild to 
moderate AD) in the overall study.  Otherwise, the MMRM analysis will only include 
subjects in the Mild to Moderate AD cohort.  The comparison between placebo and active 
doses will be performed within mild to moderate AD subjects regardless of subjects included 
in the MMRM analysis.  Dunnett’s method will be used to control for multiplicity due to 
multiple comparisons.
Page 1000 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 109 of 156
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01 and 02)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild to moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to 
moderate AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 
18 months in MCI/Prodromal and mild to moderate AD subjects.  Data from early 
discontinuations will also be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild to 
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 
18 months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD 
subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 
12 and 18 months in MCI/Prodromal and mild to moderate AD subjects
Page 1001 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 110 of 156
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual E2609 concentration listings.  The PK 
Analysis Set will be used for summaries of E2609 concentrations. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in CSF will 
be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  The PK/PD relationship between plasma PK parameters with other 
biomarkers may also be explored using similar methods.
Additionally, the relationship between plasma and CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between plasma and CSF exposure to E2609 
and the change from baseline for 18 months in the ADAS-cog, the CDR, and the MMSE,
will be explored graphically.  Any emergent relationship will be explored through population 
PK/PD modeling.
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
Page 1002 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 111 of 156
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum severity (mild, moderate, or severe).  The number (percentage) of subjects with 
Page 1003 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 112 of 156
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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with treatment-
related TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.
Page 1004 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 113 of 156
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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
Page 1005 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 114 of 156
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE, CDR, and CBB (see 
Section 9.7.1.6).
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Page 1006 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 115 of 156
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 
0.15 (SUVR), respectively; this would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per 
Amendment 01)  
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in Section 9.7.1.6.2.  
The statistical power was estimated through simulation for the dose-response assumption that 
the percent reduction in change from baseline of ADCOMS at 18 months compared with 
placebo would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated 
power for the actual planned 200 mild to moderate AD subjects is approximately 80% 
assuming a 2-sided alpha of 0.05.  (revised per Amendment 01)
9.7.3
Interim Analysis
In order to make decisions about the remainder of the study as well as the full E2609 clinical 
development program, the sponsor will unblind safety, PK, and PD data on an ongoing basis 
and perform interim analyses of these data.  Investigators, other clinical site staff, subjects 
and caregivers/informants will remain blinded to study treatment.  (revised per 
Amendment 03)
An interim safety analysis will also be conducted when the first 60 subjects have completed 
12 weeks of treatment (or discontinue study drug early) in Stage A. (revised per 
Amendments 01 and 03)  
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of 
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
Page 1007 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 116 of 156
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, including MCI/Prodromal subjects from 
Stage A and Stage B).  (revised per Amendment 01)  Further interim efficacy analyses will 
be conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
Page 1008 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 117 of 156
The Mild to Moderate AD Cohort (revised per Amendment 01)  
A group sequential design will be used for the Mild to Moderate AD cohort.  (revised per 
Amendment 01)  This design includes 3 looks, 2 interim looks (when 60% and 80% 
information fractions are achieved) and 1 final look.  The information fraction is the number 
of assessments in all treatment arms divided by the total number of expected assessments.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the 
first, second, and final analyses, respectively.  If the actual information fraction during the 
interim analyses is different from 60% or 80% at the interim, the efficacy boundaries will be 
adjusted based on the actual information fraction.  
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort 
based on the data for mild to moderate AD subjects available at that time. (revised per 
Amendment 01)  
Randomization into the Mild to Moderate AD cohort will remain at a fixed schedule 
throughout Stage B.  (revised per Amendment 01)  
The interim analyses in the Mild to Moderate AD cohort will be conducted by an
independent analysis group.  (revised per Amendment 01)  
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 
active doses for the first 100 MCI/Prodromal subjects randomized, including those 
randomized from both Stage A and Stage B).  Thereafter, randomization probabilities to each 
treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  (revised 
per Amendment 01)  
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)  
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 
dose groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to 
moderate AD subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 
50 mg E2609) at a 1:1:1 ratio. (revised per Amendment 01)  
Page 1009 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 118 of 156
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 1010 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 119 of 156
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology 
2007;68:1588-95.
Page 1011 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 120 of 156
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on 
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 1012 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 121 of 156
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 1013 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 122 of 156
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
25.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 1014 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 123 of 156
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 1015 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 124 of 156
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, 
ECGs, rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 1016 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 125 of 156
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 1017 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 126 of 156
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 CTA 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 CTA 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 CTA 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.
Page 1018 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 127 of 156
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.
Page 1019 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 128 of 156
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Male:
>44 – 3.0 x 44
Female:
>3.0 – 5.032
Male
>3.0 – 5.044
Female:
>5.0 – 20.032
Male:
>5.0 – 20.044
Female:
>20.032
Male:
>20.044
Page 1020 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 129 of 156
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 1021 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 130 of 156
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 1022 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 131 of 156
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and 
Listing 6.  Medications permitted with restrictions are listed in Listing 7, Listing 8, and 
Listing 9.  These may not be all-inclusive listings.  Please contact the medical monitor(s) if 
the investigators have any questions or concerns regarding any medication not listed that 
your subjects may be taking before enrollment or start during the course of the E2609-G000-
202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 9 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 1023 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 132 of 156
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Blaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Antinausea/ nausea
Page 1024 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 133 of 156
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 1025 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 134 of 156
Listing 2 Prohibited Medications Within 7 Days (or 5 Half-lives, Whichever is Longer) 
Before Randomization and Until after the Last Treatment Visit)
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Anticoagulants
Adeporin
Normiflo
Alteplase, tPA
Activase, Cathflo Activase
Anisindione
Miradon
Antithrombin III
ATryn, Thrombate III
Argatroban
Argatroban
Bivalirudin
Angiomax
Dabigatran
Pradaxa
Dalteparin
Fragmin
Danaparoid
Orgaran
Dicumarol
Dicumarol
Enoxaparin
Lovenox
Fondaparinux 
Arixtra
Heparin Sodium
Monoject
Lanoteplase
Lanoplase
Lepirudin
Refludan
Pentosan 
polysulfate sodium
Elmiron
Reteplase
Retavase, Retevase
Staphylokinase
Eskinase, Heberkinasa Kabikinase, Streptase, Thrombosolv, Zykinase
Streptokinase
Streptase
Tenecteplase
TNKase
Tinzaparin
Innohep
Urokinase
Abbokinase, Kinlytic
Warfarin
Coumadin, Jantoven
Antiplatelet drugs
Aspirin and Plavix 
(revised per 
Amendment 01)
For subjects who consent to CSF sample collection:  Aspirin or clopidogrel is permitted 
in all subjects.  Aspirin and clopidogrel in combination is not permitted.  (revised per 
Amendments 01 and 02)
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, is permitted.  (revised per Amendment 02)
Page 1026 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 135 of 156
Note:  This list is not exhaustive.
Page 1027 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 136 of 156
Listing 3 Prohibited Medications Within 5 Half Lives or 60 Days, Whichever is 
Longer, Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
Page 1028 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 137 of 156
Listing 4 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 1029 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 138 of 156
Listing 5 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 1030 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 139 of 156
Listing 6 Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 1031 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 140 of 156
Permitted Prior/Concomitant Medications
Listing 7
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Follow-Up Visit 2
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 1032 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 141 of 156
Listing 8
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph 
SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
PRN = Pro re nata
Page 1033 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 142 of 156
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 8.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 1034 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 143 of 156
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Flunitrazepam
Rohypnol
Page 1035 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 144 of 156
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 1036 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 145 of 156
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 1037 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 146 of 156
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 1038 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 147 of 156
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 1039 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 148 of 156
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Relaxed
Page 1040 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 149 of 156
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 1041 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 150 of 156
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 1042 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 151 of 156
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
Page 1043 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 152 of 156
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or 
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)    
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and Table
12), and a 10% cut value is applied to each of the 3 CD markers of interest the following 
age-adjusted LLN values are generated: 
Page 1044 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 153 of 156
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 1045 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 154 of 156
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 1046 of 1658


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 155 of 156
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product 
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 1047 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 03)
E2609-G000-202
Eisai
FINAL (v5.0):  06 Feb 2016
Confidential
Page 156 of 156
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof-of-Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 1048 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page i of xii
REVISION HISTORY
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
Grammatical, typographical, and 
formatting changes 
Throughout
Mandatory nature of CSF
collection in study changed to
voluntary.  This change impacts 
the timing and details of the 
PK/PD interim analyses.  It also 
impacts the nature of the 
CSF-related objectives, which 
will now be identified as 
exploratory.
To increase rate of subject 
consent into the study

Synopsis –
o Secondary Objectives
o Exploratory Objectives
o Study Design
o Exclusion Criterion No. 12
o Pharmacokinetic 
Assessments
o Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments
o Safety Assessments
o Secondary Endpoints
o Exploratory Endpoints
o Analysis for the Secondary 
Endpoints
o Analysis for the Exploratory 
Endpoints
Section 5.3
Section 8.2
Section 8.3
Section 9.1
Section 9.1.1.2
Section 9.2.6
Section 9.3.2
Section 9.4.6
Section 9.5.1.3.3
Section 9.5.1.4
Section 9.5.1.5.12
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Section 12, Listing 2
Extended the range of cognitive 
impairment in delayed recall that 
would be considered inclusionary 
for the study and removed the 
eligibility nature of the cognitive 
Original delayed recall 
aspect of inclusion 
criterion #1 was 
considered to be too 
restrictive and was 

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.1

Section 9.3.2
Page 1049 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page ii of xii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
tests repeated at the Baseline 
Visit.
unnecessarily screening 
out subjects with 
MCI/prodromal AD.  The 
eligibility nature of the 
cognitive tests repeated at 
the Baseline Visit has been 
removed in order to 
simplify the requirements 
of the pretreatment period 
for the study.
Addition of historical amyloid 
PET scans for determination of 
eligibility for the study.  Subjects 
with historical PET scans will not 
be part of the longitudinal PET 
analyses and therefore will not 
require a second PET scan at 
either Visit 18 or ED.
To provide the sites with 
greater operational 
flexibility and reduce 
subject burden.

Synopsis –
o
Inclusion/
Exclusion Criteria
o
Pharmacodynamic, 
Pharmacogenomic, and 
Other Biomarker 
Assessments

Section 9.1.1

Section 9.2.5.3

Section 9.3.1

Section 9.5.2, Table 6 and 
Table 7
Added the need for safety 
laboratory tests to be repeated for 
subjects whose pre-treatment 
period is extended due to active 
infection. 
To ensure that all baseline 
safety laboratory tests are 
repeated for subjects 
whose pretreatment period 
is extended.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2

Section 9.5.2, Table 6
Clarified that exclusion criterion 
No. 22 (exclusion of subjects with 
CD4, CD8, or CD19 absolute 
counts below the LLN) applies to 
flow cytometry tests conducted at 
both the Screening and the 
Baseline Visits.  Furthermore, 
LLNs that are adjusted for the 
subject population under study
will be used.
It was not clear that 
Exclusion Criterion No. 22 
applied to both the 
Screening and the Baseline 
Visits.  The LLNs for 
CD4, CD8 and CD19 
absolute counts require 
adjustment for the age of 
the patient population in 
this study.

Synopsis –
o
Inclusion/
Exclusion Criteria

Section 9.3.2
Provided additional detail 
regarding scope of Exclusion 
Criterion No. 34 which excludes 
subjects with hypopigmentation 
conditions.
Added to provide clarity 
for the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2
Revised number of clinical sites 
For feasibility purposes

Synopsis – Sites
Page 1050 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page iii of xii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
from 30 to 40

Section 6

Section 9.1

Section 9.3
Relaxed the requirement for the 
cognitive assessments at 
Screening Visit 1 to be conducted 
in a certain order and revised the 
recommended order in which the 
assessments could be conducted.
To provide the sites with 
greater operational 
flexibility.

Section 9.1.1, Figure 2

Section 9.5.1.3.1

Section 9.5.2, Table 6
Clarify the duration for which the 
Safety magnetic resonance 
imaging (MRI) scan, the amyloid 
PET scan and the lumbar puncture 
(LP) collected CSF conducted at 
Screening are considered valid.
To provide sites with 
greater operational 
flexibility, particularly for 
re-screening of screen fail 
subjects.

Section 9.1.1
Clarify that for subjects meeting 
criteria for weekly monitoring of 
lymphocyte subsets, these can be 
accommodated within the 
scheduled clinic visits during the 
early stages of the treatment 
period of the study.
To provide operational 
clarity to the sites.

Synopsis –
o
Exclusion Criteria

Section 9.3.2

Section 9.3.3

Section 9.5.1.5.3
Added the requirement for 
complete blood counts (CBC) 
with differentials to be performed 
whenever repeat or unscheduled 
flow cytometry tests are 
performed.   
Such that CBC data are 
available at all times when 
flow cytometry data is 
available.

Section 9.3.3, Table 1

Section 9.5.2, 
o Table 6
o Table 7
Added 30 day window to the 
duration of the pre-treatment 
period if required for medical or 
operational reasons.
To provide the sites with 
greater operational 
flexibility.

Synopsis –
o
Study Design
o
Duration of Treatment

Section 9.1, Figure 1

Section 9.1.1

Section 9.1.1.2

Section 9.5.2, Table 6
Page 1051 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page iv of xii
Revisions to Version 3.0
New version/date: Version 4.0, 05 Nov 2015
Change
Rationale
Affected Protocol Sections
Clarified the timing of the start of 
the Randomization Phase
Clarification 

Section 9.1.1

Section 9.1.2

Section 9.5.2, 
o Table 6
o Table 7
Increased number of 
MCI/Prodromal or mild to 
moderate AD subjects screened 
for entry into the study
To reflect the higher 
screen failure rate than 
originally anticipated

Synopsis –
o
Number of Subjects
Removal of CD127 cell surface 
markers
FoxP3 is the most 
accepted marker to 
measure T regulatory cells 
and additional assessment 
of CD127 is not required.

Section 9.5.1.5.3, Table 4

Section 9.5.2.1
Made the clinical biochemistry, 
urinalysis, CBC, lymphocyte 
subsets, and immunoglobulin tests 
mandatory at Visit 20, regardless 
of clinical significance at Visit 19.
For more comprehensive 
safety data at the second 
follow-up visit.

Section 9.5.2, Table 7
Corrected reference to Exclusion 
Criterion No. 20 (and not to 
Exclusion #19) in footnote to 
Table 6 and Table 7 regarding 
timing of Visit 3 in relation to 
Visit 2.
Correction

Section 9.5.2, 
o Table 6
o Table 7
Revised details regarding 
prohibited antiplatelet drugs 
To distinguish between 
those subjects who consent 
to CSF sample collection 
and those who do not

Appendix 2, Listing 2
Page 1052 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page v of xii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1, Section 9.1.1

Figure 1

Section 9.2.1, Section 9.2.2, 
Section 9.2.3

Section 9.2.5.3 and Section 9.2.5.4

Section 9.3, Section 9.3.1, 
Section 9.3.2

Section 9.4.1, Section 9.4.3, 
Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2, Section 9.7.1.1.3

Section9.7.1.4

Section 9.7.1.6, Section 9.7.1.6.2, 
Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.2.2

Section 9.7.3

Section 9.7.4
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.1
Page 1053 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page vi of xii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis – Inclusion/Exclusion 
Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 
capacity to consent themselves.

Section 5.3
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis – Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Page 1054 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page vii of xii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis – Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 1055 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page viii of xii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis - Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5.1 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis – Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis – Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
Inclusion/Exclusion  Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and 
International Normalized Ratio
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
Inclusion/Exclusion Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
For subjects who discontinue study 
drug prematurely, conduct efficacy 
To facilitate efficacy analyses, 
which are based on longitudinal 

Synopsis –Study Design 

Section 9.1.2.2

Section 9.3.3
Page 1056 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page ix of xii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
modeling for all subjects

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol. The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis - Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis - Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis – Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline,
during treatment, and posttreatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis - Assessments,

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 

Synopsis - Concomitant 
Drug/Therapy

Section 7.1
Page 1057 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page x of xii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
plasma levels of E2609

Section 9.4.7

Appendix 2(Listing 6)
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis – Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis – Analysis of 
Primary Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis – Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (excl criterion 8) but a blood 
draw for Vit B12 was inadvertently 
missed out of Table 6 in protocol 
version 1.

Synopsis – Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5.1
Page 1058 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page xi of xii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis – Study Endpoints

Section 9.7.1.2
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.6

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Page 1059 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page xii of xii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 1060 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 13 of 168
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-
of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and 
Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to 
Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (Amendment 01)
V4.0
05 Nov 2015 (Amendment 02)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 1061 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 14 of 168
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-
fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, Dose-Finding 
Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive 
Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia Due to Alzheimer’s Disease (revised per Amendment 01)
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 40 sites, United States only (revised per Amendments 01 and 02)
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  Approximately 42 months from initiation of Stage B (revised per Amendment 01)
Phase 2
Objectives
Primary Objectives
1.
To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect (ED90)
for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 18 months of 
treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease (referred to as MCI/Prodromal throughout the protocol)
2.
To assess the safety (including immunological and hematological parameters) and tolerability of 
daily dosing with E2609 in MCI/Prodromal subjects and in subjects with Mild to Moderate 
Dementia due to Alzheimer's Disease (referred to as mild to moderate AD throughout the 
protocol) (revised per Amendment 01)
Secondary Objectives (revised per Amendment 02)
1.
To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects, as measured by volumetric magnetic 
resonance imaging (vMRI)
2.
To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 18 months 
in mild to moderate AD subjects (revised per Amendment 01)
Page 1062 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 15 of 168
Exploratory Objectives
(revised per Amendments 01 and 02)
1.
To explore the effect of E2609 compared with placebo on the derived ADCOMS following 
12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2.
To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 12 and 
18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3.
To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects and in mild to moderate AD 
subjects (revised per Amendment 02)
4.
To explore the effects of E2609 compared with placebo on clinical status at various time points 
during 18 months of treatment, and during post-treatment follow-up, in MCI/Prodromal and mild 
to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional Activities 
Questionnaire)
f.
The International Shopping List Task (ISLT)
5.
To explore the effects of E2609 compared with placebo on various biomarkers in MCI/Prodromal 
and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after 18 months 
of treatment
b.
Plasma and CSF amyloid, and CSF β-amyloid converting enzyme 1 (BACE1) measurements
during 18 months of treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain volume and 
total ventricular volume at 6, 12, and 18 months of treatment and during post-treatment
follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission tomography 
(PET)
6.
To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and mild to 
moderate AD subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7.
To explore the relationship between the treatment effects of E2609 on the ADCOMS and its 
effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and mild to 
moderate AD subjects
Study Design
This will be a multicenter placebo-controlled, double-blind, parallel-group, randomized, dose-finding 
study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common set of inclusion 
criteria, consistent with the National Institute on Aging – Alzheimer’s Association (NIA-AA) clinical 
research criteria for Mild Cognitive Impairment (MCI) due to Alzheimer’s Disease (AD) or mild to 
moderate AD, will be required for all subjects.  In addition, the MCI due to AD population will also 
be consistent with the research criterion for “Prodromal AD” in that episodic memory will be 
impaired on a list learning task (ISLT).  As the non-demented subjects will be consistent with the 
criteria for both MCI due to AD and Prodromal AD they will be identified as MCI/Prodromal 
Page 1063 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 16 of 168
subjects in this protocol. The diagnosis of MCI/Prodromal AD or mild to moderate AD will be based 
on both clinical and biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an interim 
evaluation of the safety and tolerability of chronic dosing with E2609 (after the first 60 randomized 
subjects have completed 12 weeks of treatment or have discontinued study drug early) before 
expanding enrollment to include a larger number of subjects in Stage B.  (revised per Amendment 01)
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective of 
whether they were recruited during Stage A or Stage B.  Bayesian response adaptive randomization 
will be used in the MCI/Prodromal cohort only during Stage B.  All mild to moderate AD subjects 
will be included in the efficacy evaluations for that cohort.  (revised per Amendment 01)
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if required
[revised per Amendment 02]) includes a Screening Visit (Visit 1) and a Baseline Visit (Visit 2).  All 
screening assessments (within 4 distinct tiers) must be completed, and eligibility to continue in the 
study confirmed, before any baseline assessments commence.  Following successful completion of
the Prerandomization Phase, eligible subjects will be randomized and will enter the Randomization 
Phase, which will consist of 2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 
12 weeks).
Stage A
Stage A will be limited to approximately 40 sites in the United States. (revised per Amendments 01 
and 02)  Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 4 treatment groups within 
each of the 2 clinical populations.  (revised per Amendment 01) In addition to the placebo group, 
3 E2609 doses will be used to reduce CSF amyloid β levels by approximately 25% (5 mg), 50%
(15 mg), and 75% (50 mg) from baseline, respectively, at steady state.  PK/pharmacodynamic (PD) 
modeling has shown that these doses should achieve these targets when administered once daily (QD) 
with food, and these doses will be evaluated based on the 4-week assessment of CSF Aβ(1-x) from 
subjects who provide voluntary consent for CSF measurement.  (revised per Amendment 02)
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In addition, 
approximately every 3 months from the time the first subject is randomized during Stage A, an 
independent data safety monitoring board (DSMB; including at least 1 immunologist) will review all 
safety data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
review as to whether any change(s) to the study are necessary.  Unless the DSMB recommends 
otherwise, randomization of subjects into Stage A will continue until 60 subjects have been 
randomized and dosed.  (revised per Amendment 01)
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who consent to 
provide CSF samples at Baseline and after 4 weeks of study drug.  These data will be used to evaluate
the CSF PD effects of E2609 doses, where PD is measured as reductions from baseline in CSF 
Aβ(1-x) levels. (revised per Amendments 01 and 02)  The mean percentage change from baseline in 
CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of E2609 and its 90% confidence 
interval will be derived.  In addition, exploratory PK/PD modeling will be conducted.  This PK/PD 
modeling will use the observed PK and PD data from Stage A and will relate the average steady state 
plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline after 
4 weeks of dosing.  (revised per Amendment 02)
Once 60 subjects in Stage A have completed at least 12 weeks of treatment (or discontinued study 
drug early) an interim safety analysis will be conducted by Eisai and the DSMB. (revised per 
Page 1064 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 17 of 168
Amendment 01) Subjects in Stage A will continue study drug while the DSMB reviews all the 
available safety data, but randomization of additional subjects will not take place (ie, recruitment into 
Stage B will not commence) until the safety analysis is completed by the DSMB.  
If there are safety signals with one of the E2609 dose groups that would require dose adjustment, 
changes to dose will be reflected in an amendment to the protocol.  Information on how these subjects 
will be handled in the primary analysis will be described in the Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  (revised per 
Amendment 02)  Stage B will enroll, randomize, and dose additional eligible subjects up to a 
maximum of 500 MCI/Prodromal and up to a maximum of 200 mild to moderate AD. The final total 
number of MCI/Prodromal subjects will depend upon whether the prespecified criteria for either early 
success or futility are met. (revised per Amendment 01) Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment to the study is completed; 
following this the DSMB will meet approximately every 6 months.  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort will 
include 3 doses of E2609 (5, 15, and 50 mg QD) whereas the Mild to Moderate AD cohort will only 
include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort only during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according to a 
fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  (revised per 
Amendment 01)   The remaining subjects in the MCI/Prodromal cohort in Stage B will then be 
randomized according to response adaptive randomizations based on the ADCOMS results using the 
Bayesian interim efficacy analyses.  The mild to moderate AD subjects will be randomized according 
to a fixed schedule (1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B. (revised per 
Amendment 01)
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an Early 
Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up Visits will also
be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when clinical 
efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18) if these visits have 
not already been performed.  At these visits, only the clinical efficacy assessments (MMSE, CDR, 
ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  Subjects who discontinue early from study 
drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study 
drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after the last dose of 
study drug (Visit 19) and a second 12 weeks after the last dose of study drug (Visit 20).  If clinically 
indicated, more frequent safety assessments can be conducted as part of unscheduled visits during the 
posttreatment Follow-Up period.
Page 1065 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 18 of 168
Number of Subjects

Stage A:  Approximately 400 MCI/Prodromal or mild to moderate AD subjects will be 
screened to provide 60 randomized subjects (target of 15 subjects per treatment arm).  There 
will be no limit to the number of subjects randomized from either clinical cohort.  (revised per 
Amendments 01 and 02)

Stage B:  Up to approximately 2100 MCI/Prodromal subjects will be screened to provide up to 
500 randomized subjects.  The final number of MCI/Prodromal subjects will depend upon 
whether the prespecified criteria for either early success or futility are met.  In addition, up to 
approximately 835 subjects with mild to moderate AD will be screened to provide up to 
200 randomized mild to moderate AD subjects.  The final number of mild to moderate AD 
subjects randomized in Stage B will depend upon the number of mild to moderate AD subjects 
previously randomized during Stage A. (revised per Amendment 01)
Page 1066 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 19 of 168
Inclusion Criteria
1.
Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD dementia and 
is "staged" or classified as either MCI or mild to moderate dementia  and also complies with the 
following: (revised per Amendment 01)
Required at Screening Visit 1:
(revised per Amendment 02)  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition from 
the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on the 
ISLT.  Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted norms in 
delayed recall on the ISLT plus impairment of at least 1 SD from age-adjusted norms in at 
least 1 other computerized learning and memory test (ISLT immediate recall, or 1 of the
learning and memory components of the CBB). (revised per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2.
Amyloid positive PET image based on centralized PET scan reading; an historical amyloid 
positive PET scan may be used if conducted within the previous 12 months and provided that the 
scan and result are considered acceptable by the central PET reading group (revised per 
Amendment 02)
3.
Male or female, age 50 to 85 years, inclusive at time of consent
4.
Must have an identified caregiver or informant who is willing and able to provide follow-up 
information on the subject throughout the course of the study.  This person must, in the opinion 
of the investigator, spend sufficient time with the subject on a regular basis such that the 
caregiver or informant can reliably fulfill the study requirements and must provide separate 
written consent.  The caregiver or informant need not be living in the same residence as the 
subject.  If the caregiver or informant is not residing with the subject, the investigator has to be 
satisfied that the subject can contact the caregiver or informant readily during the times when the 
caregiver or informant is not with the subject.  If in doubt about whether a subject's care 
arrangements are suitable for inclusion, the investigator should discuss this with the medical 
monitor.  At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at the 
time of the visit.  The investigator will determine whether attendance in person is required or 
whether telephone contact will be suitable and will base this determination upon the functional 
ability of the subject among other factors.  
5.
If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a stable 
dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, with no plans for 
dose adjustment in the foreseeable future.  Treatment-naïve subjects can be entered into the study 
but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry 
into the study.
6.
Must have been on stable doses of all other permitted chronically used concomitant medications 
(ie, not related to their cognitive decline) for at least 4 weeks before randomization.
Exclusion Criteria
1.
Any neurological condition that may be contributing to cognitive impairment above and beyond 
that caused by the subject’s AD pathology, including any co-morbidities detected by neurological 
examination or magnetic resonance imaging (MRI)
Page 1067 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 20 of 168
2.
Modified Hachinski Ischemic Scale >4 
3.
History of transient ischemic attacks or stroke within 12 months of Screening
4.
A history of epilepsy.  Subjects with a history of seizures (not including a history of simple 
febrile seizures in childhood) within 10 years of Screening.  Subjects with disturbance likely to 
be due to seizures within 5 years of Screening.  
5.
Significant pathological findings on the brain MRI at Screening, including but not limited to:  
more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), any 
microhemorrhage which is symptomatic, a single macrohemorrhage greater than 10 mm at 
greatest diameter, an area of superficial siderosis, evidence of vasogenic edema, greater than 
3 lacunar infarcts or a single infarct >2 cubic centimeters involving a major vascular territory, 
evidence of severe microangiopathy, evidence of cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, infective lesions or space-occupying lesions (however, 
lesions diagnosed as arachnoid cysts and < 1cm in diameter at their greatest diameter need not be 
exclusionary) or brain tumors (eg, meningioma). (revised per Amendment 01)
6.
Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that 
could, in the opinion of the investigator, confound the MCI/Prodromal or mild to moderate AD 
diagnosis or could interfere with study assessments or procedures (revised per Amendments 01
and 02)
7.
A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8.
Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for the 
testing laboratory) at Screening
9.
Thyroid stimulating hormone above the normal range.  Other tests of thyroid function with results 
outside the normal range should only be exclusionary if they are considered clinically significant 
by the investigator.  This applies to all subjects regardless of whether or not they are taking 
thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of normal 
(ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or Baseline.  
Subjects with Gilbert’s syndrome need not be excluded.
11. Any contraindications to MRI or PET scanning, including cardiac pacemaker/ defibrillator or 
ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for 
use in MRI scanners).  Subjects who require sedation for MRI or PET scanning as per local 
guidelines need not be excluded.
12. Any contraindications to lumbar puncture for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not limited to 
obesity).  Only applicable to subjects consenting to CSF sample collection (revised per 
Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders (including 
subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous TB 
exposure (eg, positive tuberculin skin test, interferon gamma release assay or other locally 
accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
Page 1068 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 21 of 168
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the timing of 
randomization can be extended (up to 4 weeks) to allow the infection to resolve; psychometric 
tests (eg, MMSE, CDR) and safety laboratory tests conducted at Visit 2 must be repeated.  
(revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or 
ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease 
where the condition is considered to be stable and adequately controlled by inhaled steroids 
need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded 
(topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test conducted 
1 week after the initial test.  The population-adjusted LLN for CD4 (T helper cells), CD8 
(cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 74 cells/µL
respectively. (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the Investigator 
and the Medical Monitor agree that the finding is not clinically significant.  The assessment of 
clinical significance will include, but not be limited to, evidence of clinical immunodeficiency.  
The discussion with the Medical Monitor should include a detailed review of medical history of 
infections, clinical and laboratory findings. (revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or clinically 
laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or Baseline 
as demonstrated by average QTc interval from triplicate electrocardiograms (ECGs).  A history 
of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) considered 
clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP >100 mmHg 
or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart disease, 
clinically significant valvular heart disease) that are not stably and adequately controlled, or 
uncompensated heart failure (New York Heart Association Class III and Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; 
Page 1069 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 22 of 168
these do not exclude the subject).  Subjects who had malignant neoplasms but who have had at 
least 5 years of documented evidence of no active disease before Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably 
controlled, or which, in the opinion of the investigator(s), could affect the subject’s safety or 
interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying disease 
causing hypopigmentation is not necessary for exclusion if the clinical presentation is consistent 
with such a condition.
Hypopigmentation associated with scarring need not be exclusionary.  
(revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  Subjects 
who test positive in the urine drug screen need not be excluded if in the clinical opinion of the 
investigator, this is due to the subject taking prior/concomitant medications for a medical 
condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation 
questions 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at 
Screening, or at the Baseline Visit; or has been hospitalized or treated for suicidal behavior in the 
past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section of the 
protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study.  Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the principal investigator this operation does not interfere with study procedures and subject 
safety.
39. Participation in any other interventional clinical study related to cognitive impairment within 
6 months before Screening unless it can be documented that the subject was in a placebo 
treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device within 
60 days or 5 half-lives of the investigational medication (whichever is longer) preceding 
informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or to the 
PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human chorionic 
gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or Baseline.  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study treatment period and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study treatment period or for 28 days after study 
drug discontinuation.
Page 1070 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 23 of 168

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use the same 
contraceptive during the study treatment period or for 28 days after study drug 
discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically [ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 
1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or not practicing 
highly effective contraception throughout the study period or for 28 days after study drug 
discontinuation).  No sperm donation is allowed during the study period or for 28 days after study 
drug discontinuation.
Study Treatments
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets to match 
E2609 will be of identical appearance.  Each subject will receive 2 tablets, which when combined 
will make up the required doses of E2609 (see below) or placebo, to be administered orally QD with 
food.  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised per Amendment 01)

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo (revised 
per Amendment 01)

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo.  
(revised per Amendment 01)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 2 years, 
comprising: 

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days, plus an additional 
window of up to 30 days if required (revised per Amendment 02)
(In subjects who have an active infection within 4 weeks of the planned randomization date, 
the duration of the pre-randomization phase can be extended by up to 4 weeks to allow 
additional time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Page 1071 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 24 of 168
Concomitant Drug/Therapy
The following agents are not permitted before randomization (specific timeframes are shown below) 
and throughout the study until after the last treatment visit (see Appendix 2 for a detailed listing of 
these agents):  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives or 
7 days (whichever is longer) before randomization

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization

Live vaccines are not permitted within 3 months before randomization.  This does not apply 
to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for a 
period of 5 half-lives or 60 days (whichever is longer) before randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be included in the 
primary analyses: 

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who change their 
dose of AChEI or memantine while on study, will be allowed to continue in the study, but their 
clinical efficacy data will be censored from the time of drug initiation for the primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications that 
are administered as short courses of treatment or which are to be used intermittently as 
needed

Medications that are used as needed, rather than on a stable daily basis, and which are central 
nervous system (CNS) active and may affect cognitive function, are not permitted during a 
period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if, in the opinion of the investigator,
this will not interfere with study procedures or subject safety, and are not prohibited above.  If the 
subject initiates treatment for co-morbidities with a (non-prohibited) drug that may affect cognitive 
function, the subject should not have cognitive assessments performed until the dose has been stable 
for at least 4 weeks.
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of selected 
items (12 total) from 3 fully validated and well established clinical tools, the ADAS-cog (4 items), 
the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should be administered in full in the 
Page 1072 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 25 of 168
morning, or, if not possible, consistently at the same time of day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be used since it 
is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and place, 
registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery: A computer-based battery comprising 4 cognitive tests:  
1.
Detection – a simple reaction time test.  Speed of response is the measure.
2.
Identification – a simple choice reaction time test.  Speed of response is the measure.
3.
One Card Back – a simple working memory test.  Accuracy of response is the measure.
4.
One Card Learning – a visual learning and memory test.  Accuracy of response is the measure.
International Shopping List Task: The ISLT is a verbal learning and episodic memory test assessing 
both immediate and delayed recall.  
Functional Assessment Questionnaire: The FAQ has 10 items concerned with performing daily tasks 
necessary for independent living.  Either a caregiver or informant or the subject provides performance 
ratings on 10 complex activities of daily living performed within the preceding 4 weeks.  
Volumetric Magnetic Resonance Imaging: vMRI will be used to evaluate disease modification, 
including the change from Baseline in terms of the measured hippocampal volume based upon the 
centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood samples will be collected for the determination of the concentrations of E2609. For subjects 
who consent to CSF sample collection, CSF samples will be collected for the determination of E2609 
concentrations.  (revised per Amendment 02)  Analyses of metabolite concentrations may be 
performed depending on emerging data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Brain atrophy will be measured by vMRI: see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), total tau (t-tau), and p-tau will be measured in subjects 
who consent to CSF sample collection (revised per Amendment 02).  BACE1 levels and activity in 
CSF will also be measured in subjects who consent to CSF sample collection (revised per 
Amendment 02).  Other exploratory biomarkers (eg, miRNA) may also be evaluated in plasma and/or 
CSF.
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period have amyloid deposition in the brain.  An historical amyloid positive PET scan may 
be used, if conducted within the previous 12 months and provided that the scan and result are 
considered acceptable by the central PET reading group. (revised per Amendment 02)  Longitudinal 
amyloid PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only 
be conducted on subjects with Screening PET scans performed for this study (ie, historical scans 
cannot be used for the longitudinal analyses) and will only be conducted through to the time at which 
acceptable 18-month PET scans have been obtained for at least 25 subjects per treatment arm for each 
amyloid PET ligand used. (revised per Amendment 02)
Page 1073 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 26 of 168
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4 homozygous 
or heterozygous status versus non-carriers and NAT2 status will be used in the statistical analysis to 
determine the effects on treatment response and safety.  Remaining genomic DNA may also be stored 
for up to 15 years to be used to examine the role of DNA sequence variability on the absorption, 
distribution, metabolism, and elimination of E2609, development of AEs, as well as the underlying 
AD.  Variations in E2609 exposure or the occurrence of AEs observed in the study population may be 
evaluated by correlation of single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory reports and 
assessing AEs separate from the site staff responsible for the efficacy assessments, particularly for the 
CDR. (revised per Amendment 01) Routine safety assessments will include the monitoring and 
recording all AEs and SAEs, monitoring of hematology, blood chemistry, and urinalysis, 
measurement of vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might indicate signals of 
possible drug abuse potential will require a more detailed follow-up.  Subjects reporting AEs relating 
to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of 
these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be measured (by 
a centralized laboratory) every week for the first month, every 2 weeks for the next 2 months (Months 
2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  Thereafter, they will be monitored 
every 3 months until the end of the Treatment Period and at both Follow-Up Visits.  Serum IgG, IgA, 
and IgM will be monitored monthly for the first 3 months, at 6, 12, and 18 months, and at both 
Follow-Up Visits.  
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, and 
posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a reviewing 
dermatologist at baseline and at 3-month intervals during the Treatment Period.  These assessments
will specifically include evaluation of any areas of depigmentation or rash.  Subjects will also be 
questioned by the investigator at each visit to identify any changes that might represent a 
drug-induced rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed 
to contact the investigator if they see any lesions or other symptoms that might be associated with a 
drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood and DNA samples will be taken and stored for all subjects, and CSF 
samples will be taken and stored for all subjects who consent to CSF sample collection (revised per 
Amendment 02).  These samples may be tested for exploratory biomarkers associated with study drug 
or disease, or in the event that a subject develops AEs that warrant further investigation (eg, to test if 
a subject with a treatment-emergent infection was exposed to any suspected infective agents before
treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months during the 
Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans are to be performed 
as clinically necessary.  MRI acquisition and interpretation will be organized centrally to ensure 
reproducibility and consistency between units involved.  
Full neurological examinations will be performed at Baseline, at 6, 12, and 18 months, and at both 
Follow-Up Visits, by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations.  The neurological examinations will include muscle strength 
Page 1074 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 27 of 168
testing and assessment of cranial nerves including olfaction as well as other parts of the CNS.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy assessment.  
Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at 
regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. An 
additional examination will be conducted if the subject experiences visual disturbances during the 
course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid chromatography 
method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF Aβ(1-42), tau, and 
p-tau will be performed using ELISAs.
BACE1 levels and activity may be measured using a customized assay.  Substrates of BACE1 
inhibition may also be explored using Western blots or other amenable methodology if clinical 
observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the Bayesian 
methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects
Secondary Endpoints
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal subjects as 
measured by vMRI

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects  (revised 
per Amendment 01)
Exploratory Endpoints
(revised per Amendments 01 and 02)
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to moderate 
AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD subjects 
as measured by vMRI
Page 1075 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 28 of 168

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects and in mild to moderate AD subjects  (revised per Amendment 02)

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months: 
ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and mild to moderate 
AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months of 
treatment, and during posttreatment follow-up in MCI/Prodromal and mild to moderate AD 
subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 and, 
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and mild 
to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic factors 
(including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD subjects
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 1 dose 
of study drug and have baseline and at least 1 postdose primary efficacy measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who sufficiently comply 
with the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 plasma 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian adaptive 
design.  Frequent interim analyses will be performed to assess the probability of early success and 
futility and to make early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the derived 
ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria if the 
probability that the ED90 at 18 months of treatment achieves 25% improvement over placebo 
is at least 80%.  Early success is achieved before all MCI/Prodromal subjects complete 
18 months of treatment and can only be determined after at least 200 MCI/Prodromal
subjects have been randomized.  If early success is declared before full randomization, the 
Page 1076 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 29 of 168
randomization of new MCI/Prodromal subjects will stop but subjects already randomized 
into the study will receive the full 18 months of treatment (following confirmation from the 
Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if the 
probability that the ED90 is better than placebo by the clinically significant difference of 25% 
is less than 5% at 18 months of treatment.  The statistical futility boundary is binding; if the 
statistical futility boundary is crossed the study will be considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if an 
ED90 at 18 months treatment has at least an 80% probability of achieving 25% improvement 
over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01): All mild to moderate AD subjects 
will be included in the efficacy evaluations of the Mild to Moderate AD cohort.   The analysis of the 
Mild to Moderate AD cohort is based on the group sequential design.  Interim analyses in the Mild to 
Moderate AD cohort will only be performed after the MCI/Prodromal cohort crosses the early 
success boundary.  The early efficacy signal based on the change from baseline of ADCOMS at 
18 months is defined as crossing the interim-analysis boundaries for overwhelming efficacy in the 
mild to moderate AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets 
alpha spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and final 
analyses, respectively, according to 2 planned interim analyses at the 60% and 80% information 
fraction. (revised per Amendment 01)
Analysis for the primary endpoint 
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the prespecified 
censoring rule applied.  The primary endpoint is the change from baseline to 18 months in the derived 
ADCOMS.  The dose-response of the primary endpoint is modelled with a first-order normal 
dynamic linear model, where Normal and Inverse-Gamma priors are used.  The primary efficacy 
analysis will calculate the Bayesian posterior probability that the dose identified is the most likely 
ED90 dose that achieves 25% improvement over the placebo arm.  At each interim analysis and the 
final analysis, 2 Bayesian probabilities will be summarized for each active dose: the probability it is
the ED90 dose and the probability of achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, CDR, CBB, ISLT, and 
FAQ), subjects will be censored at the time of initiation of treatment with AChEIs or memantine, if 
they were not on these medications at the time of Baseline cognitive assessment (Visit 2), and will be 
censored at the time of dose adjustment of AChEIs or memantine if they were already on stable 
treatment with these medications at the time of Baseline cognitive assessment (Visit 2).  The value of 
the primary endpoint for censored subjects will be imputed using data up to the censoring time and 
Bayesian longitudinal modeling.
Sensitivity analyses of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods described above 
as well as conventional statistical methods.  The following additional Bayesian analyses will be 
conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as primary 
analysis. This is an intent-to-treat analysis without any censoring.  
Page 1077 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 30 of 168

In case of early success, the primary analysis as well as the above sensitivity analyses will be 
repeated after all subjects have completed 18 months of treatment or have been lost to 
follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with repeated 
measures (MMRM) on the change from baseline in the derived ADCOMS at 18 months.  The model 
will include treatment groups, randomization stratification variables (the presence or absence of 
ongoing treatment with AChEIs or memantine or both, and ApoE4 status), and baseline ADCOMS as 
covariates.  Other covariates such as adjusted hippocampal volume will be studied.  These analyses 
will be performed as sensitivity analyses on the FAS as well as the per protocol set, and as such, no 
multiplicity adjustments will be made to account for the interim analyses.  In case of early success, 
the conventional analyses will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint:  (revised per Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 18 months in 
mild to moderate AD. If there is no treatment group-by-population interaction in the overall study, 
the MMRM analysis will include all subjects (MCI/Prodromal or mild to moderate AD) in the overall 
study.  Otherwise, the MMRM analysis will only include subjects in the Mild to Moderate AD 
cohort.  The comparison between placebo and active doses will be performed within mild to moderate 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will be used 
to control for multiplicity due to multiple comparisons.
Analysis for exploratory endpoints
(revised per Amendments 01 and 02)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild to 
moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to moderate 
AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal and mild to moderate AD subjects. Data from early discontinuations will 
also be included.  (revised per Amendment 02)

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, CBB, 
and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal and mild
to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 
4 weeks and 18 months of treatment, and during posttreatment follow-up in MCI/Prodromal 
and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild to 
Page 1078 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 31 of 168
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months in 
MCI/Prodromal and mild to moderate AD subjects 

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 18 months 
of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between each 
treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship between the 
following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in imaging 
biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 and 18 months in 
MCI/Prodromal and mild to moderate AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to assess the 
effect of ApoE status in this relationship.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF and plasma
biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1 will be assessed and 
data will be presented graphically.  Baseline levels and changes in t-tau and p-tau will be correlated 
with changes in CSF Aβ(1-42), imaging markers, and ApoE4 status.  Summary statistics for CSF 
biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in plasma and CSF 
will be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  Additionally, the relationship between CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between CSF exposure to E2609 and the change
from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  Any emergent relationships will be explored through 
population PK/PD modeling.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of subjects 
enrolled in this study.  Further information is in the “Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments” section.  Details of pharmacogenomic testing may be provided and 
reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical and neurological examinations, and dermatological assessments), 
out-of-normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, 
suicidality (C-SSRS), and results of the sleep questionnaire, along with the change from baseline in 
laboratory safety test variables, ECGs, safety MRI, and vital sign measurements will be summarized 
Page 1079 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 32 of 168
by treatment group using descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 
[natural killer cells] and CD14 [macrophages]) and regulatory T cells will be summarized in the same 
manner as other laboratory parameters.  Mean lymphocyte subsets and the mean change from 
baseline in lymphocyte subsets will also be displayed graphically over time by dose.  Serum IgG, 
IgM, IgA will be measured and summarized in the same manner as other laboratory parameters.
Interim Analyses
An interim safety analysis will be conducted when the first 60 subjects have completed 12 weeks of 
treatment (or discontinue study drug early) in Stage A. (revised per Amendment 01)
The MCI/Prodromal Cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be conducted 
by an independent committee that has expertise with Bayesian adaptive design in clinical studies.  An 
unblinded external independent analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim analysis 
and response adaptive randomization process through review of efficacy data.  In addition, the 
committee will act in an independent advisory capacity to monitor the Bayesian interim analysis 
outcomes according to the early success and futility boundaries prespecified in the protocol.  The 
committee will not be charged with any subject safety issues; this will remain the responsibility of the 
DSMB.  The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  The study may be stopped for safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal subjects 
have been randomized into the study (ie, including MCI/Prodromal subjects from both Stage A and 
Stage B).  (revised per Amendment 01) Further interim efficacy analyses will be conducted after 
each additional 50 MCI/Prodromal subjects have been randomized, up to a maximum of 
500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 500 subjects 
randomized).  If the study reaches full randomization, additional interim analyses will be conducted 
every 3 months until all subjects complete 18 months of treatment.  The study will be monitored for 
futility at each interim analysis.  Starting at the 200 subjects’ interim analysis, the study will be 
monitored for success at each interim analysis.  Each interim analysis will be conducted on data for 
the derived ADCOMS.  
If the predefined early success criteria are met during the recruitment period, further recruitment and 
enrollment of MCI/Prodromal subjects into the study will stop (following confirmation from the 
Sponsor’s Senior Management) and all currently randomized subjects will complete the full 18 
months of treatment.  No further interim analyses will be conducted after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized into the 
study and the treatment of subjects already randomized into the study will stop and the study will be 
declared as “failed”.  All subjects will be monitored for safety for 3 months following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all subjects 
will complete 18 months of treatment.  Interim efficacy analyses will be conducted every 3 months 
after full randomization is reached to assess futility and early success until all subjects complete 
18 months of treatment.  After full randomization, all study subjects will stop treatment only in the 
event of futility.  
Page 1080 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 33 of 168
The Mild to Moderate AD Cohort (revised per Amendment 01)
A group sequential design will be used for the Mild to Moderate AD cohort.  This design includes 
3 looks, 2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the first, 
second, and final analyses, respectively.  If the actual information fraction during the interim analyses 
is different from 60% or 80% at the interim, the efficacy boundaries will be adjusted based on the 
actual information fraction.  If early success in the MCI/Prodromal cohort is not achieved before the 
final analysis that is performed when all subjects have completed 18 months treatment, then only a 
final analysis will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort based on 
the data for mild to moderate AD subjects available at that time.  (revised per Amendment 01)
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses
for the first 100 MCI/Prodromal subjects randomized, including  those randomized from both Stage 
A and Stage B).  Thereafter, randomization probabilities to each treatment group will be updated at 
each interim analysis, such that the randomization probability will be increased for the placebo group 
and dosage groups that represent the potential target dose (ED90), and simultaneously decreased for 
other active arms.  (revised per Amendment 01)
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 dose 
groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to moderate AD 
subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 50 mg E2609) at a 1:1:1 
ratio. (revised per Amendment 01)
Stratification (revised per Amendment 01)
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or memantine 
or both (yes or no). (revised per Amendment 01)
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by means of 
simulations.  Extensive study simulations have shown that a total of 500 subjects will be sufficient to 
demonstrate that the most likely ED90 dose achieves a 25% improvement over placebo with a 
probability of at least 80% in the interim and final analyses.  There is at least a 90% probability of 
study success for the dose response scenarios where treatment was considered to have a clinically 
meaningful treatment effect.  Simulations have also shown that if there is no obvious dose effect, the 
probability of falsely claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects per 
group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 1 null 
hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s method with 1-sided 
Page 1081 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 34 of 168
alpha of 0.05.  The statistical power was estimated through simulation for a moderate dose-response 
assumption that the percent reduction in change from baseline of total hippocampal volume compared 
with placebo would be 15%, 20%, and 25% corresponding to the 3 doses, respectively.  The 
estimated power for actual planned study sample size is 78% at 18 months assuming an attrition rate 
of 20% at 18 months.  Under a stronger dose-response assumption (ie, the percent reduction in 
change from baseline of total hippocampal volume compared with placebo is twice as much as that in 
the moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those for 
vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of change from baseline was estimated at 0.33 and a reasonable mean difference between 
treatment and placebo was estimated as 0.25 (standardized uptake value ratio [SUVR]).  Assuming a 
moderate dose-response, the best dose would achieve a difference of 0.25 (SUVR) and the middle 
and low doses would achieve a difference of 0.2 and 0.15 (SUVR), respectively, it would require a 
total of 100 subjects from all 4 arms at 18 months to achieve 80% power.
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per Amendment 01)
ADCOMS at Month 18: The null hypothesis is that there is no difference between active dose and 
placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in the secondary analysis 
section.  The statistical power was estimated through simulation for the dose-response assumption 
that the percent reduction in change from baseline of ADCOMS at 18 months compared with placebo 
would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated power for the 
actual planned 200 mild to moderate AD subjects is approximately 80% assuming a 2-sided alpha of 
0.05. (revised per Amendment 01)
Page 1082 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 35 of 168
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE...................................................................................................................13
2
CLINICAL PROTOCOL SYNOPSIS.............................................................................14
3
TABLE OF CONTENTS.................................................................................................35
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................40
5
ETHICS............................................................................................................................43
5.1
Institutional Review Boards/Independent Ethics Committees ..............................43
5.2
Ethical Conduct of the Study.................................................................................43
5.3
Subject Information and Informed Consent...........................................................44
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................46
7
INTRODUCTION ...........................................................................................................47
7.1
Nonclinical and Clinical Safety Data.....................................................................48
8
STUDY OBJECTIVES....................................................................................................51
8.1
Primary Objectives.................................................................................................51
8.2
Secondary Objectives.............................................................................................51
8.3
Exploratory Objectives ..........................................................................................51
9
INVESTIGATIONAL PLAN..........................................................................................53
9.1
Overall Study Design and Plan..............................................................................53
9.1.1
Prerandomization Phase...............................................................................56
9.1.1.1
Screening Period..................................................................................57
9.1.1.2
Baseline Period ....................................................................................59
9.1.2
Randomization Phase...................................................................................59
9.1.2.1
Treatment Period..................................................................................59
9.1.2.2
Early Discontinuation ..........................................................................60
9.1.2.3
Follow-up Period .................................................................................60
9.2
Discussion of Study Design, Including Choice of Control Groups.......................60
9.2.1
Overview......................................................................................................60
9.2.2
Rationale for Study Population....................................................................61
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................62
9.2.4
Rationale for Clinical Endpoints..................................................................63
9.2.5
Rationale for Biomarkers.............................................................................64
9.2.5.1
Overall Rationale .................................................................................64
9.2.5.2
Soluble Biomarkers in CSF .................................................................64
9.2.5.3
Amyloid PET .......................................................................................65
9.2.5.4
vMRI....................................................................................................65
9.2.6
Clinical Risks and Mitigation Strategy........................................................66
Page 1083 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 36 of 168
9.3
Selection of Study Population................................................................................68
9.3.1
Inclusion Criteria .........................................................................................68
9.3.2
Exclusion Criteria ........................................................................................69
9.3.3
Removal of Subjects from Therapy or Assessment.....................................73
9.4
Treatments..............................................................................................................77
9.4.1
Treatments Administered.............................................................................77
9.4.2
Identity of Investigational Product...............................................................77
9.4.2.1
Chemical Name and Formula of E2609...............................................78
9.4.2.2
Comparator Drug .................................................................................78
9.4.2.3
Labeling for Study Drug......................................................................78
9.4.2.4
Storage Conditions...............................................................................78
9.4.3
Method of Assigning Subjects to Treatment Groups...................................79
9.4.4
Selection of Doses in the Study...................................................................79
9.4.5
Selection and Timing of Dose for Each Subject..........................................81
9.4.6
Blinding........................................................................................................81
9.4.7
Prior and Concomitant Therapy...................................................................82
9.4.8
Treatment Compliance.................................................................................83
9.4.9
Drug Supplies and Accountability...............................................................83
9.5
Study Assessments.................................................................................................85
9.5.1
Assessments.................................................................................................85
9.5.1.1
Demography.........................................................................................85
9.5.1.2
Baseline Assessments ..........................................................................85
9.5.1.2.1
Medical History and Physical Examinations.................................85
9.5.1.2.2
Viral Testing ..................................................................................86
9.5.1.2.3
B12 Testing....................................................................................86
9.5.1.2.4
TB Exposure Testing .....................................................................86
9.5.1.2.5
Urine Drug Testing ........................................................................86
9.5.1.3
Efficacy Assessments...........................................................................86
9.5.1.3.1
Psychometric Assessments ............................................................86
9.5.1.3.2
Volumetric MRI.............................................................................87
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................88
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................88
9.5.1.4.1
Pharmacokinetic Assessments .......................................................88
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................89
9.5.1.5
Safety Assessments..............................................................................91
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..91
Page 1084 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 37 of 168
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................94
9.5.1.5.3
Laboratory Measurements .............................................................95
9.5.1.5.4
Vital Signs and Weight Measurements..........................................96
9.5.1.5.5
Physical Examinations...................................................................97
9.5.1.5.6
Electrocardiograms ........................................................................97
9.5.1.5.7
Safety MRI.....................................................................................97
9.5.1.5.8
Dermatological Assessment...........................................................98
9.5.1.5.9
Neurological Examination .............................................................98
9.5.1.5.10
Pregnancy Test...............................................................................99
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................99
9.5.1.5.12
Biomarker Samples........................................................................99
9.5.1.5.13
Ophthalmic Examinations..............................................................99
9.5.2
Schedule of Procedures/Assessments ........................................................100
9.5.2.1
Schedule of Procedures/Assessments ................................................100
9.5.2.2
Description of Procedures/Assessments Schedule.............................109
9.5.3
Appropriateness of Measurements.............................................................110
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations............................................................110
9.5.4.1
Reporting of Serious Adverse Events................................................110
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................111
9.5.4.3
Reporting of Events Associated with Special Situations...................111
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................111
9.5.4.3.2
Reporting of Study-Specific Events.............................................112
9.5.4.4
Expedited Reporting ..........................................................................112
9.5.4.5
Breaking the Blind.............................................................................112
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................113
9.5.5
Completion/Discontinuation of Subjects...................................................113
9.5.6
Abuse or Diversion of Study Drug ............................................................114
9.5.7
Confirmation of Medical Care by Another Physician ...............................114
9.6
Data Quality Assurance .......................................................................................114
9.6.1
Data Collection ..........................................................................................114
9.6.2
Clinical Data Management ........................................................................115
9.7
Statistical Methods...............................................................................................115
9.7.1
Statistical and Analytical Plans..................................................................115
9.7.1.1
Study Endpoints.................................................................................115
Page 1085 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 38 of 168
9.7.1.1.1
Primary Endpoint.........................................................................115
9.7.1.1.2
Secondary Endpoints ...................................................................115
9.7.1.1.3
Exploratory Endpoints .................................................................116
9.7.1.2
Definitions of Analysis Sets...............................................................116
9.7.1.3
Subject Disposition............................................................................117
9.7.1.4
Demographic and Other Baseline Characteristics .............................117
9.7.1.5
Prior and Concomitant Therapy.........................................................118
9.7.1.6
Efficacy Analyses ..............................................................................118
9.7.1.6.1
Primary Efficacy Analysis...........................................................119
9.7.1.6.2
Secondary Efficacy Analyses ......................................................120
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................121
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................122
9.7.1.7.1
Pharmacokinetic Analyses...........................................................122
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................122
9.7.1.8
Safety Analyses..................................................................................123
9.7.1.8.1
Extent of Exposure.......................................................................123
9.7.1.8.2
Adverse Events ............................................................................123
9.7.1.8.3
Laboratory Values........................................................................124
9.7.1.8.4
Vital Signs....................................................................................125
9.7.1.8.5
Electrocardiograms ......................................................................125
9.7.1.8.6
Other Safety Analyses..................................................................126
9.7.2
Determination of Sample Size ...................................................................126
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................126
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort 
(revised per Amendment 01) .............................................................127
9.7.3
Interim Analysis.........................................................................................127
9.7.4
Other Statistical/Analytical Issues .............................................................129
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................130
10
REFERENCE LIST .......................................................................................................131
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....135
11.1
Changes to the Protocol .......................................................................................135
11.2
Adherence to the Protocol....................................................................................135
11.3
Monitoring Procedures.........................................................................................135
11.4
Recording of Data................................................................................................136
11.5
Identification of Source Data...............................................................................136
11.6
Retention of Records............................................................................................137
Page 1086 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 39 of 168
11.7
Auditing Procedures and Inspection....................................................................137
11.8
Handling of Study Drug.......................................................................................137
11.9
Publication of Results ..........................................................................................138
11.10 Disclosure and Confidentiality ............................................................................138
11.11 Discontinuation of Study .....................................................................................138
11.12 Subject Insurance and Indemnity.........................................................................139
12
APPENDICES ...............................................................................................................140
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................75
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................76
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................80
Table 4
Clinical Laboratory Tests...........................................................................95
Table 5
Lymphocyte Subtyping..............................................................................96
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .......................................................................101
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20)...............................................................104
Table 8
Summary of Blood and CSF Sample Volumes........................................109
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202............................................................54
Figure 2
Assessments to be Performed at Screening by Tier...................................58
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................140
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........143
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 157
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................160
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-G000-202:  
Justification for a Population-Adjusted Approach...................................163
Page 1087 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 40 of 168
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg 1-
42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBC
complete blood count
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carobxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
ECG
electrocardiogram
Page 1088 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 41 of 168
Abbreviation
Term
eCRF
electronic case report form
ED
early discontinuation
ED90
lowest effective dose that achieves 90% of the greatest treatment effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
Page 1089 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 42 of 168
Abbreviation
Term
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OF
O’Brien-Fleming 
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 1090 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 43 of 168
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR)
regarding clinical studies, including Part 50 and Part 56 concerning informed subject 
consent and IRB regulations and applicable sections of US 21 CFR Part 312
Page 1091 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 44 of 168

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for 
studies conducted within any European Union country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion.  If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 1092 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 45 of 168
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
All subjects will also be asked to provide written consent for cerebrospinal fluid (CSF) 
sampling at Baseline and after receiving study drug for 4 weeks and 18 months (or at Early 
Discontinuation).  This consent for CSF sample collection is not required for study eligibility. 
(revised per Amendment 02)
Page 1093 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 46 of 168
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 125 investigational sites globally (40 sites in the United States for 
Stage A and 125 sites globally for Stage B). (revised per Amendments 01 and 02)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 1094 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 47 of 168
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010, Lu, et 
al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, thus 
accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild to moderate dementia due to Alzheimer’s Disease (referred to as mild to moderate AD
throughout the protocol) to determine whether the effects of E2609 in this later stage 
population are comparable with those established in the MCI/Prodromal population within 
Page 1095 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 48 of 168
this same study. (revised per Amendment 01)  In the MCI/Prodromal population, Bayesian 
response adaptive randomization design is used with frequent interim analyses to continually 
update randomization allocation based on emerging clinical endpoint data.  This approach 
allows for ongoing assessment of drug futility or evidence of early success and can mitigate 
the risks associated with larger and longer studies required to demonstrate clinical efficacy 
by leading to more efficient study termination or early advancement to a Phase 3 program.  
Results from this study will guide both the decision to move into Phase 3 development and 
the selection of the dose strengths to be taken into Phase 3.  Moreover, this study is intended 
to be supportive for registration in the MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5, 15, and 50 mg) administered once daily (QD) for 18 months.  In the mild to moderate AD 
population, this study will compare placebo and 2 oral doses of E2609 (15 and 50 mg) 
administered QD for 18 months.  To date, the longest duration of dosing with E2609 is 
14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  (revised per 
Amendment 01)  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the first 60 randomized subjects have completed 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  The study also includes a 
number of exclusion criteria, specific blinded safety monitoring procedures and safety 
criteria for discontinuation of study drug in light of the preclinical and clinical safety data 
collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50-mg dose only, aged 
65 to 85 years).  
Page 1096 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 49 of 168
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the pharmacokinetic (PK) levels of E2609 and the 
pharmacodynamic (PD) effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
Page 1097 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 50 of 168
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 1098 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 51 of 168
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  (revised per Amendment 02)
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild to moderate AD subjects (revised per Amendment 01)  
8.3
Exploratory Objectives
(revised per Amendments 01 and 02)  
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after 4 weeks and 18 months of treatment in MCI/Prodromal and mild to moderate AD 
subjects (revised per Amendment 02)
Page 1099 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 52 of 168
4. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, in 
MCI/Prodromal and mild to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b. The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d. The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
5. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
posttreatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
6. To characterize the population PK of E2609 in MCI/Prodromal and mild to moderate AD 
subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
7. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild to moderate AD subjects
Page 1100 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 53 of 168
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study 202 is a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per Amendment 
01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) before expanding enrollment to include a larger number of subjects in Stage B.  
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective 
of whether they were recruited into Stage A or Stage B.  Bayesian response adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B.  All mild to 
moderate AD subjects will be included in the efficacy evaluation of that cohort. (revised per 
Amendment 01)  
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  
The Prerandomization Phase (up to 60 days, plus an additional window of up to 30 days if 
required [revised per Amendment 02]) will consist of a Screening Visit and a Baseline Visit.  
Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and Figure
2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
In Stage A, all subjects (MCI/Prodromal and mild to moderate AD) will be randomized 
1:1:1:1 to 4 treatment groups (E2609 at 3 doses or placebo).  In Stage B, randomization of 
MCI/Prodromal subjects will start off at a 1:1:1:1 ratio (E2609 at 3 doses or placebo), until a 
total of 100 MCI/Prodromal subjects have been randomized.  Remaining subjects in the 
MCI/Prodromal cohort will be randomized according to response adaptive randomizations 
based on the ADCOMS results using the Bayesian interim efficacy analyses.  Subjects with 
mild to moderate AD who are recruited in Stage B will be randomized in a 1:1:1 ratio to 
3 treatment groups (E2609 at 2 doses or placebo). (revised per Amendment 01)  
Page 1101 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 54 of 168
An overview of the study design is presented in Figure 1 .
Figure 1
Design of Study E2609-G000-202
(revised per Amendments 01 and 02 )
R = randomization.
Stage A
Stage A will be limited to approximately 40 sites in the United States.  (revised per 
Amendments 01 and 02) Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 
4 treatment groups within each clinical cohort.  (revised per Amendment 01)  There will be 
no Bayesian adaptation during Stage A.  In addition to the placebo group, 3 doses of E2609
will be used to reduce CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 
75% (50 mg) from baseline, respectively, at steady state.  PK/PD modeling shows these
doses should achieve these targets when administered QD with food and will be evaluated
based on the 4-week assessment of CSF Aβ(1-x) from subjects who provide voluntary
consent for CSF measurement. (revised per Amendment 02) (see Section 9.4.4).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Page 1102 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 55 of 168
Stage A, an independent DSMB (including at least 1 immunologist) will review all safety 
data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
review as to whether any change(s) to the study are necessary.  Unless the DSMB 
recommends otherwise, randomization of subjects into Stage A will continue until 
60 subjects have been randomized and dosed.  (revised per Amendment 01)  
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who consent 
to provide CSF samples at Baseline and after 4 weeks of study drug.  These data will be used 
to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions from 
baseline in CSF Aβ(1-x) levels (see Section 9.4.4).  (revised per Amendments 01 and 02)  
The mean percentage change from baseline in CSF Aβ(1-x) measured after 4 weeks of 
treatment for each dose of E2609 and its 90% confidence interval will be derived.  In 
addition, exploratory PK/PD modeling will be conducted.  This PK/PD modeling will use the 
observed PK and PD data from Stage A and will relate the average steady state plasma 
concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction from baseline after 
4 weeks of dosing.  (revised per Amendment 02)
Once 60 subjects in Stage A have completed at least 12 weeks of treatment (or discontinued 
study drug early) an interim safety analysis will be conducted by Eisai and the DSMB.  
(revised per Amendment 01)  Subjects in Stage A will continue study drug while the DSMB 
reviews all the available safety data, but randomization of additional subjects will not take 
place (ie, recruitment into Stage B will not commence) until the safety analysis is completed 
by the DSMB.  At the time of this interim safety analysis, some subjects will have more than 
12 weeks of safety data.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol. Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are evaluated.  
(revised per Amendment 02) Based on data from Stage A, the protocol will be reviewed and 
may be amended before beginning Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment in the study is 
completed; following this the DSMB will meet approximately every 6 months.
Stage B will be conducted globally and will enroll, randomize, and dose additional eligible 
subjects up to a maximum of 500 MCI/Prodromal subjects and up to a maximum of 200 mild 
to moderate AD subjects. The final total number of MCI/Prodromal subjects will depend 
upon whether the prespecified criteria for either early success or futility are met.  (revised per 
Amendment 01)  
Page 1103 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 56 of 168
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5, 15, and 50 mg QD), whereas the Mild to Moderate AD 
cohort will only include 2 doses of E2609 (15 and 50 mg QD).  (revised per Amendment 01)  
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according 
to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  
(revised per Amendment 01)  The remaining subjects in the MCI/Prodromal cohort in Stage 
B will then be randomized according to response adaptive randomizations based on the 
ADCOMS results using the Bayesian interim efficacy analyses.  The mild to moderate AD 
subjects will be randomized according to a fixed schedule (1:1:1 placebo; 15 mg E2609; 
50 mg E2609) throughout Stage B. (revised per Amendment 01)  
Interim efficacy analyses are planned and are discussed in Section 9.7.3.
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days (plus an additional window of up to 30 days if 
required [revised per Amendment 02]) and a window of no more than 10 days is to be 
observed between the completion of all Baseline Visit assessments (including confirmation 
of eligibility following all Baseline Visit assessments) and randomization into the study at 
Visit 3 (revised per Amendment 02).  Thus, the Prerandomization Phase will last for up to 
60 days, plus an additional window of 30 days if required (revised per Amendment 02).  The 
series of assessments conducted during this phase will determine eligibility for 
randomization into the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization the clinician will provide a judgment on the classification of a subject as either 
MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This judgment
may be discussed and reviewed with the Sponsor or Sponsor’s representative, as necessary.
Results of the Screening safety magnetic resonance imaging (MRI) will be valid for 90 days 
from the date of scanning.  Results of the lumbar puncture (LP) from subjects who 
voluntarily consent for CSF measurement will be valid for 90 days from the date of testing.  
Results of Screening PET scans conducted specifically for this study and for use in the 
longitudinal analyses will also be valid for 90 days from the date of scanning.  These 
assessments will not need to be repeated should the subject be randomized within that time 
period either under their original subject identification number or under a new re-screening 
subject identification number.  Historical PET scans used for determination of eligibility only 
(ie, not used for the longitudinal analyses) are valid for 12 months.  (revised per Amendment 
02)
Page 1104 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 57 of 168
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Page 1105 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 58 of 168
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The recommended order of assessments at Screening is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  (revised per Amendment 02)  The investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and will 
base this determination upon the functional ability of the subject among other factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).  An historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and provided that the scan and result 
are considered acceptable by the central PET reading group.  If an historical amyloid positive PET scan is being used, it
should be submitted to the central PET reading group after the subject has completed and passed all Tier 1 assessments.   
(revised per Amendment 02)  
Page 1106 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 59 of 168
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days, plus an additional window of up to 30 days
if required. (revised per Amendment 02)
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination will be 
performed.  A urine pregnancy test will be conducted for females of childbearing potential.  
Blood will be collected from all subjects for clinical chemistry and hematology, lymphocyte 
subset analyses, Ig analyses, and PD assessments.  Blood samples will be collected and 
stored for determination of a subject’s previous exposure to infective pathogens in the event 
of AEs that warrant further investigation occurring at a later point in the study.  Psychometric 
assessments will be administered to the subject in the order stated in Table 6.  The caregiver 
or informant needs to be present at this visit.  The Columbia Suicide Severity Rating Scale 
(C-SSRS) will also be administered (Section 9.5.1.5.11).
For subjects who consent to CSF sample collection, CSF will be obtained at this visit for PK 
and PD assessments (see Section 9.5.1.5.3).  (revised per Amendment 02)
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase no more than 10 days after completion of the Baseline Visit 
assessments and confirmation of the eligibility of the subject based on the results of all the 
Baseline Visit assessments (revised per Amendment 02).
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Page 1107 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 60 of 168
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
9.1.2.3
Follow-up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Oct 2019 (end date will 
depend on actual recruitment rate).

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The 2 stage design of the study allows for the safety and tolerability of E2609 to be assessed 
in a limited number of subjects (n=60) before expanding recruitment into a larger population 
of subjects. (revised per Amendment 01)  
Page 1108 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 61 of 168
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild to 
moderate AD to determine whether the effects of E2609 in this later stage population are 
comparable with those established in the MCI/Prodromal population within this same study 
(see Section 9.2.3 for discussion of the Bayesian design used in this study). (revised per 
Amendment 01)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of 
well-established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (see Section 9.2.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; and a cognitive 
and functional assessment, which is the change from baseline in the derived ADCOMS at 
18 months of treatment in mild to moderate AD subjects.  (revised per Amendments 01 and 
02)  Exploratory endpoints including assessments of efficacy, safety and other biomarkers
are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
Page 1109 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 62 of 168
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in 
mild to moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 
2 different subject populations that differ in terms of AD severity before the initiation of 
large Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild to moderate AD will be assessed as a “nested” population that does not 
follow the Bayesian adaptive design.  It was not considered appropriate to have a Bayesian 
design for both cohorts as this would have substantially increased the overall study sample 
size, delayed analyses of dose response, and would have added background “noise” for the 
Page 1110 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 63 of 168
comparison of subjects with MCI/Prodromal AD compared with those with mild to moderate 
AD. Data from each cohort will be analyzed independently for the purposes of decision 
making.  A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild 
to moderate AD confounding the results for the primary population (MCI/prodromal).  
(revised per Amendment 01)  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
Page 1111 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 64 of 168
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility 
inclusion criterion)

To evaluate safety (principally by MRI)

To evaluate a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term (revised per 
Amendment 02)

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
Page 1112 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 65 of 168
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both total tau (t-tau) and p-tau are sensitive markers of axonal and neuronal degeneration 
(t-tau) and neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel 
with disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have 
been correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful 
predictors of cognitive decline and progression to dementia due to AD.  Rebalancing 
dysregulated amyloid production early in the process may positively affect the 
neurodegenerative process and thus affect these markers and benefit the disease trajectory.  
Therefore, monitoring these markers in conjunction with amyloid imaging may provide 
further supportive evidence of efficacy.  
Baseline levels of Aβ(1-42), tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be used in this study for 2 primary reasons: 1) to confirm the 
presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted on subjects with Screening PET scans performed for this study (ie, 
historical scans cannot be used for the longitudinal analyses) and will only be conducted until
18-month PET scans of acceptable quality have been obtained for at least 25 subjects per 
treatment arm for each amyloid PET ligand used.  (Revised per Amendment 02)
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
Page 1113 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 66 of 168
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
regions during the early stages of disease and progresses towards the anterior regions of the 
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Two-stage study design:  there will be a pause in recruitment after 60 subjects have
been randomized to study drug (Stage A).  Only after the safety of E2609 in these 
first 60 subjects (consisting of up to 12 weeks data for the later subjects and longer 
dosing periods for the earlier subjects) has been reviewed by the DSMB and 
considered acceptable, will randomization of further subjects into the study 
commence (Stage B). (revised per Amendment 01)

Immunology-related and infection-related exclusion criteria
Page 1114 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 67 of 168

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and 
percentage change from baseline), skin rash, reoccurrence of herpes virus infections 
including any oral herpes, genital herpes or shingles, other infections, MRI changes, 
ECGs, and pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course 
of the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of
vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will 
be questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and posttreatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood and DNA samples will be taken and stored for all 
subjects, and CSF samples will be taken and stored for all subjects who consent to 
CSF sample collection (revised per Amendment 02).  These samples may be tested in 
the event that a subject develops AEs that warrant further investigation (eg, if a 
subject develops a treatment-emergent infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals
during the Treatment Period, and at the final Follow-Up Visit.

Full neurological examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  Details of the neurological 
examination are given in Section 9.5.1.5.9.
Page 1115 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 68 of 168

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using 
the detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, 
Baseline, and at regular intervals during the Treatment and Follow-Up Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 2 off-treatment Follow-Up
visits (4 and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated.

An ophthalmic examination will be conducted at Baseline and if the subject 
experiences visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will randomize 60 eligible MCI/Prodromal or mild to moderate AD subjects at 
approximately 40 sites in the United States (revised per Amendment 02).  There will be no 
restriction to the number of subjects from either population.  Stage B will randomize subjects
at approximately 125 sites globally.  Recruitment will continue in Stage B until a maximum 
of approximately 500 MCI/Prodromal subjects and up to a maximum of approximately 200 
mild to moderate AD subjects have been randomized (including subjects randomized during 
Stage A).  The final total number of MCI/prodromal subjects will depend upon whether the 
prespecified criteria for either early success or futility are met.  The number of mild to 
moderate AD subjects randomized in Stage B will depend upon the number of mild to 
moderate AD subjects randomized during Stage A. (revised per Amendment 01)
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Required at Screening Visit 1:  
(revised per Amendment 02)
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT. Alternatively, cognitive impairment of at least 0.5 SD from age-adjusted 
Page 1116 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 69 of 168
norms in delayed recall on the ISLT plus impairment of at least 1 SD from 
age-adjusted norms in at least 1 other computerized learning and memory test (ISLT
immediate recall, or 1 of the learning and memory components of the CBB).  (revised 
per Amendment 02)
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading; an historical 
amyloid positive PET scan may be used if conducted within the previous 12 months and 
provided that the scan and result are considered acceptable by the central PET reading 
group (revised per Amendment 02)
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitor (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
Page 1117 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 70 of 168
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and < 1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors (eg, 
meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could, in the opinion of the investigator, confound the MCI/Prodromal or 
mild to moderate AD diagnosis or could interfere with study assessments or procedures 
(revised per Amendments 01 and 02)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to LP for CSF sampling (eg, lower spinal malformation on 
physical examination, local spinal infection or other abnormality, including but not 
limited to obesity).
Only applicable to subjects consenting to CSF sample collection
(revised per Amendment 02)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
Page 1118 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 71 of 168
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests (eg, MMSE, CDR) and safety laboratory tests conducted at 
Visit 2 must be repeated.  (revised per Amendment 02)
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
population-adjusted LLN at Screening or Baseline and confirmed by a repeat test 
conducted 1 week after the initial test.  The population-adjusted LLN for CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are 396, 157, and 
74 cells/µL respectively. See Appendix 5.  (revised per Amendment 02)
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
Page 1119 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 72 of 168
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo).  Diagnosis of an underlying 
disease causing hypopigmentation is not necessary for exclusion if the clinical 
presentation is consistent with such a condition.
Hypopigmentation associated with 
scarring need not be exclusionary.  (revised per Amendment 02)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
Page 1120 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 73 of 168
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 
28 days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 28 days after study drug discontinuation.
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 4 and 12 weeks after the last dose of study drug (see Section 9.1.2.3).  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie, at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
Page 1121 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 74 of 168
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4
(T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation 
threshold will be set at below the level of the population-adjusted LLN
(CD4=396 cells/µL; CD8=157 cells/µL; and CD19=74 cells/µL), at a level that 
represents a greater risk of opportunistic infection in the treated population.  (revised per 
Amendment 02)  For CD4 (T helper cells) the discontinuation threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the discontinuation thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the discontinuation 
threshold as confirmed by a repeat test conducted within 1 week of the initial test will be 
discontinued from study drug.
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the population-adjusted LLN and the discontinuation threshold will have 
lymphocyte subset counts performed on a weekly basis.  (revised per Amendment 02)  
Subjects with a >33% reduction from baseline in CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts will also have lymphocyte subset counts 
performed on a weekly basis.  During the early stages of the treatment period, where 
visits are conducted weekly (ie, Visits 4, 5, 6, and 7), lymphocyte subsets are already 
scheduled to be measured on a weekly basis and so additional visits or blood draws are 
not required.  (revised per Amendment 02)  For these subjects, the decision as to whether 
the subject remains on study drug or is to be discontinued from study drug will be based 
upon clinical judgment and will take into account any clinical presentation in addition to 
the lymphocyte subset counts.  These subjects may continue with treatment if there is no 
clinical evidence of infection.  They will be discontinued from study drug if they have 
infections of a moderate to severe intensity (eg, subjects whose infections are not 
localized, or are systemically unwell, or who require systemic anti-infective drug
treatment).
Page 1122 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 75 of 168
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue or 
discontinue
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
discontinuation threshold
Retest within 1 week along with
CBC with differentials
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
discontinue study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts between 
population-adjusted LLN and discontinuation 
threshold or >33% reduction from baseline in CD4 
(T helper cells), CD8 (cytotoxic T cells), or CD19 
(B cells) absolute counts
Lymphocyte subset counts (and 
CBC with differentials) to be 
performed weekly until 
lymphocyte subset counts return 
to ≥ population-adjusted LLN 
or no more than 33% reduction 
from baseline
Decision will be based upon 
lymphocyte subset counts and 
clinical judgment
LLN = lower limit of normal, CBC = complete blood count.  (table revised per Amendment 02)
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the population-adjusted LLN and the 
discontinuation thresholds or have shown >33% reduction from baseline, subjects with 
infections of moderate intensity will be discontinued from study drug (eg, subjects whose 
infections are not localized, or subjects who are systemically unwell, or who require 
systemic anti-infective drug treatment).  All subjects with infection who are discontinued 
from study drug will be followed for a period of 12 weeks or until the infection resolves/
stabilizes or until the CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) 
absolute counts have returned to greater than population-adjusted LLN (whichever comes 
latest). (revised per Amendment 02)
Page 1123 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 76 of 168
Table 2
Study Drug Actions for Lymphocyte Subset 
Absolute Counts and Infection
Criterion
Severity of Infection
None
Mild
Moderate
Severe
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
below discontinuation threshold
If confirmed 
with repeat 
testing within 
1 week, then 
discontinue
study drug.
Discontinue 
study drug
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
between population-adjusted LLN and 
discontinuation threshold or >33% 
reduction from baseline in CD4 (T helper 
cells), CD8 (cytotoxic T cells), or CD19 
(B cells) absolute counts
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
Discontinue 
study drug
Discontinue 
study drug
CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts 
always > population-adjusted LLN and no 
reduction from baseline >33%
May continue 
treatment with 
study drug 
unless 
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug 
unless
discontinuation 
is clinically 
indicated
May continue 
treatment with 
study drug unless 
discontinuation is 
clinically indicated 
(See (e) for 
exception)
Discontinue 
study drug
LLN = lower limit of normal.  Table revised per Amendment 02
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 4 and 12 weeks after the last dose of 
study drug.  They will also undertake an Unscheduled Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
be performed at approximately the time of the second Follow-Up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
Page 1124 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 77 of 168
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered in Stage A and Stage B are shown below and in Figure 1.
The 2 highest E2609 doses (15 and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A, will be used for the mild to moderate AD population in Stage B.
(revised per Amendment 01)  

Stage A:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, MCI/Prodromal Cohort:  3 doses (5, 15, and 50 mg) of E2609 or placebo

Stage B, Mild to Moderate AD Cohort:  2 doses (15 and 50 mg) of E2609 or placebo.
(revised per Amendment 01)  
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-, 10-, and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5, 15, 50 mg, or placebo.  The tablets 
Page 1125 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 78 of 168
will be supplied by the Sponsor in labeled blister packs.  The product release certificates for 
E2609 and placebo will be included in the clinical study report for this protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-
4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
Page 1126 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 79 of 168
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for Stage A (all subjects), for Stage B MCI/Prodromal subjects and Stage B for mild to 
moderate AD subjects are described in Section 9.4.1. (revised per Amendment 01)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5, 15, and 50 mg QD administered as the tablet formulation with food in this study
should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% at 
steady state, respectively (Table 3).
Page 1127 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 80 of 168
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1
Activity
% Reduction 
CSF A(1-x)
5
6.2
3.3
80.3
16.2
33
15
18.6
10
240.9
36.6
56
50
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = Beta-amyloid converting enzyme, CSF = cerebrospinal fluid,  Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients. (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 400 mg (17.3% 
decrease).  No subjects had infections or drug rash while receiving E2609 100 mg QD or at 
lower doses in Study 002, whereas at 200 and 400 mg QD, 4 subjects had symptomatic 
orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The highest dose 
for Study 202 of 50 mg QD (tablet administered with food) is therefore expected to have a 
similar or better safety profile compared with the 100 mg QD capsule (administered fasted) 
in Study 002.  Specific exclusion criteria, blinded and unblinded safety monitoring 
procedures, and safety criteria for discontinuation from study drug are included in this study
in order to mitigate any immunology-related risk with E2609, particularly in light of the 
progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
In Stage A, all subjects will be randomized to receive either placebo or E2609 at 5, 15, or 
50 mg QD.  In Stage B, subjects in the MCI/Prodromal cohort will continue to be 
randomized to receive either placebo or E2609 at 5, 15, or 50 mg QD. In Stage B, subjects in 
the Mild to Moderate AD cohort will be randomized to receive either placebo or E2609 at 
15 or 50 mg QD, but not the 5-mg QD dose.  The rationale for not including an E2609 5-mg 
QD dose in the dose regimens for Stage B subjects with mild to moderate AD is that more 
Page 1128 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 81 of 168
advanced disease may require greater reduction in CSF Aβ levels for comparable effects. 
(revised per Amendment 01)  
Interim analyses of the E2609 PK and PD profiles will be performed on subjects who have 
provided CSF samples at Baseline and after 4 weeks of study drug.  These data will be used 
to evaluate the CSF PD effects of E2609 doses, where PD is measured as reductions from 
baseline in CSF Aβ(1-x) levels.  (revised per Amendments 01 and 02)  The mean percentage 
change from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment for each dose of 
E2609 and its 90% confidence interval will be derived.
In addition, exploratory PK/PD 
modeling will be conducted. This PK/PD modeling will use the observed PK and PD data 
from Stage A and will relate the average steady state plasma concentration of E2609 to 
steady state CSF Aβ(1-x) percentage reduction from baseline after 4 weeks of dosing.
(revised per Amendment 02)
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects and all personnel involved 
with the conduct and interpretation of the study, including investigators, site personnel, and 
Eisai staff will be blinded to the treatment codes (double-blind).  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
The PK/PD interim analysis to evaluate the E2609 doses to be used for Stage B will be 
conducted by an independent group (revised per Amendment 02).  Any changes to dose will 
be reflected in an amendment to the protocol and the Statistical Analysis Plan will detail how 
data will be handled in the primary analysis.  
Page 1129 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 82 of 168
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and
Listing 6.  Medications that are permitted with restrictions are listed in Listing 7, Listing 8, 
and Listing 9.
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives 
or 7 days (whichever is longer) before randomization 

Drugs which may cause QTc prolongation are not permitted for a period of 
5 half-lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2
Page 1130 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 83 of 168

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not 
permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
Page 1131 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 84 of 168

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 FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of 
the principal investigator’s current medical license (required for United States sites) 
or medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, and (e) documentation of 
returns to the sponsor.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs 
and empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and, together with unused study drugs that were shipped to the site 
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
Page 1132 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 85 of 168
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
Page 1133 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 86 of 168
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  At the Screening Visit, the recommended order of 
assessments is: MMSE, ISLT (immediate recall), CBB, ISLT (delayed recall), CBB (repeat 
CBB for additional practice), CDR, and FAQ.  The CBB may be repeated multiple times if 
required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the 
assessments are to be conducted in the following order: MMSE, CDR, ADAS-cog14, FAQ,
ISLT (immediate recall), CBB, and ISLT (delayed recall). (revised per Amendment 02)
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild to moderate AD.  (revised per Amendment 01)  
It also shows sensitivity to treatment effects with AChEIs.  The ADCOMS assesses both 
cognitive and functional domains and can be offered as a single primary clinical endpoint.  
The ADCOMS has a range from 0 to 1.97.  
Page 1134 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 87 of 168
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test where the subject presses a key when the card 
is turned face up from a pack of cards (“Has the card turned over”).  Speed of 
response is the measure.
2. Identification – a simple choice reaction time test where the subject presses 1 of 
2 keys when the card just turned face up is either a red card or a black card (“Is the 
card red”).  Speed of response is the measure.
3. One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial 
or not (“Is the previous card the same”).  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not 
in the task (“Have you seen this card before in this task”).  Accuracy of response is 
the measure.
ISLT: The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects are read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Mini Mental State Examination: A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:
The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire:
Either a caregiver or informant or the subject 
provides performance ratings (from 0 to 3) on 10 complex activities of daily living performed 
within the preceding 4 weeks.  Scores range from 0 (independent) to 30 (dependent).  
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
Page 1135 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 88 of 168
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
For subjects who consent to CSF sample collection, CSF samples will be collected by LP 
(gravity drip method) at the timepoints specified in Table 6 and Table 7 (revised per 
Amendment 02).  The CSF sample taken at the Baseline Visit will only be performed after 
subjects consent to CSF sample collection, and after confirmation of an amyloid positive 
PET scan (revised per Amendment 02). See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for the determination of the concentrations of E2609.  For 
subjects who consent to CSF sample collection, CSF samples will be collected for the 
determination of E2609 concentrations. 
(revised per Amendment 02)  Analyses of 
metabolite concentrations may be performed, depending on emerging data from other studies 
with E2609.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
Page 1136 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 89 of 168
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A second PK blood sample will be collected as close as possible in time to 
the LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the first report of an SAE or severe unexpected 
AE and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Subjects who consent to CSF sample collection will be encouraged to stay at the site after 
completion of LP for medical observation (revised per Amendment 02).  At Baseline, a CSF 
sample will be collected by LP (gravity drip method) after fasting (preferred), or at least 
2 hours after the most recent meal.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed between 4 and 
8 hours postdose and at a similar time of day (±1 hour) for each individual subject.  At visits 
where cognitive tests are also performed, if the tests are to be performed on the same day, the 
LP must be performed after the cognitive tests have been completed and the subjects should 
rest and drink some fluid to hydrate before the LP.  (revised per Amendment 01) The CSF 
sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous 
CSF sample.  The CSF sample will be used for PD assessments including but not limited to 
CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE.  The plasma sample will be used for 
Aβ(1-x) analysis and may be used for exploratory biomarker analyses (eg, miRNA).  Aβ(1-x) 
in both CSF and plasma will be measured using a commercially based enzyme-linked 
immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF Aβ(1-42), 
t-tau, and p tau will be performed using ELISAs.  BACE1 levels will be measured using 
internally developed fluorescence resonance energy transfer and ELISA based assay(s).  
Substrates of BACE1 inhibition may also be explored using Western blots or other amenable 
methodology if clinical observations warrant and if analytes can be reliably tested in samples 
collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, blood samples will be collected and stored for determination of prior 
exposure to any suspected infective agents in the event that the subject develops treatment-
emergent AEs that warrant further investigation (eg, treatment-emergent infection).  For 
subjects who consent to CSF sample collection, CSF samples from the Baseline Visit will 
also be stored for the same purpose.  (revised per Amendment 02)  Testing may include, but 
Page 1137 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 90 of 168
not be limited to, serological tests, viral titer by quantitative polymerase chain reaction, or 
human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any CSF samples
collected from subjects who consent to CSF collection will be stored for up to 15 years.  
(revised per Amendment 02)
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  An historical amyloid positive PET scan may be used if conducted within the previous 
12 months and provided that the scan and result are considered acceptable by the central PET 
reading group. (revised per Amendment 02)  Longitudinal amyloid PET imaging will also be 
conducted after 18 months of treatment (or at ED, providing the subject has received at least 
39 weeks of study drug).  Longitudinal amyloid PET imaging will only be conducted on 
subjects with Screening PET scans performed for this study (ie, historical scans cannot be 
used for the longitudinal analyses) and will only be conducted until acceptable 18-month
PET scans have been obtained for at least 25 subjects per treatment arm for each amyloid 
PET ligand used (Table 6).  (revised per Amendment 02)  PET scanning will be performed 
with a locally approved Aβ imaging agent (eg, Amyvid).
Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Page 1138 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 91 of 168
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and posttreatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not 
necessary to report every sign or symptom as a separate AE if the overall disease 
[diagnosis] is being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, discontinuation of study 
drug, or withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  For subjects 
who discontinue early from study drug but undertake further efficacy assessments, AEs will 
only be collected for 3 months after the last dose of study drug, ie, through to the second 
follow-up visit (Visit 20).  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
Page 1139 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 92 of 168
collected for 3 months after the last dose of study drug, ie, through to the second follow-up 
visit (Visit 20).  For subjects who discontinue early from study drug but continue with further 
efficacy assessments, SAEs will be solicited only for 3 months after the last dose of study 
drug, i.e. up to the 2nd follow up visit (Visit 20). However, any SAEs volunteered by 
subjects after this time point must be reported according to standard procedures.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADCOMS, ADAS-cog14, MMSE, and CBB 
(see Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment 
Period, and if this cognitive decline is considered by the investigator to be excessive relative 
to the subject’s recent AD history, this finding should be reported as an AE.
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
Page 1140 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 93 of 168
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following adverse events will require the collection of information sufficient to provide a 
detailed description of the event, treatment and outcome to the Medical Monitor for the 
study: any treatment-emergent significant laboratory abnormality; any seizures, herpes zoster 
infection, severe infection; any moderate to severe drug rash or any rash lasting more than 
72 hours (regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the second follow-up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of 
the event

The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Page 1141 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 94 of 168
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
Page 1142 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 95 of 168
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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils).
PT, PTT, and INR (Screening and Baseline only)  (revised per Amendment 02)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte subset analyses (see Table 5).  Regulatory T cells will be measured using 
CD4, CD25, and FoxP3 intracellular marker.  
PBMCs (revised per Amendment 02)
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HBsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Page 1143 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 96 of 168
Table 4
Clinical Laboratory Tests
Category
Parameters
Cerebrospinal fluid sampling
Whenever unscheduled lymphocyte subset tests are performed or whenever scheduled lymphocyte subsets are repeated, a 
CBC with differentials, must also be repeated.  (revised per Amendment 02) 
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (CD3, CD4, CD8, CD45, CD19, CD16, CD56, and CD14) 
and total lymphocyte counts will be measured in order to provide the lymphocyte subset data 
as shown in Table 5.  In addition, Regulatory T cells will be measured using CD4, CD25, and 
FoxP3 intracellular marker.  Current sponsor data supports the literature showing there is an
age-related decline in lymphocyte subsets (see Appendix 5). These data have been used to 
revise the LLNs for CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) 
absolute counts to the population-adjusted LLNs of 396, 157, and 74 cells/µL, respectively)
(revised per Amendment 02).  
Table 5
Lymphocyte Subtyping 
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
Page 1144 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 97 of 168
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
in the supine position for at least 5 minutes.
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2* Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
Page 1145 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 98 of 168
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.  MRI imaging 
will be conducted on separate days from the scheduled visits.  MRI imaging should be 
conducted within the 7 days before Visits 14, 16, and 18 and at the second Follow-Up Visit 
(Visit 20).  In the event of an Unscheduled Visit, the investigator in consultation with the 
sponsor will determine whether or not a safety MRI should be conducted.  If an ED Visit 
takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and Follow-Up Visits at 4 weeks and 12 weeks 
after the last dose of treatment.  Subjects will also undertake an Unscheduled Visit (with 
MRI) at approximately 30 days after the visit at which such MRI features were first 
identified.  Additional visits may be arranged if clinically indicated in the opinion of the 
investigator, and may occur later than 12 weeks after the final dose of study drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
Page 1146 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 99 of 168
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve.  Treatment-emergent abnormal neurological 
findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF (for subjects who consent to CSF sample collection), 
blood, and DNA samples will be collected and may be used for exploratory biomarker 
analyses, as well as tested in the event that a subject develops AEs that warrant further 
investigation.  (revised per Amendment 02)
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
Page 1147 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 100 of 168
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 1148 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 101 of 168
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/ Assessments (to be completed in a maximum of 50 days, plus an additional window of up to 30 days if 
required)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Subject informed consent for CSF sample collection (voluntary) 
X
X
Demographics
X (Tier 1)
Medical historya
X (Tier 1)
Prior / concomitant medicationsb
X (Tier 1)
X
Vital signs including weightc 
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTd
X (Tier 1)
X
MMSEd
X (Tier 1)
X
CDRd
X (Tier 1)
X
FAQd
X (Tier 1)
X
ADAS-cog14d
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGe
X (Tier 2)
X
Blood and urine for clinical laboratory testsf
X (Tier 2)
X
Blood for lymphocyte subset analysesg
X (Tier 2)
X
Blood for Ig analysesh
X (Tier 2)
X
Blood for viral screeni
X (Tier 2)
Blood for thyroid function testsj
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIk
X (Tier 3)
Amyloid PET scanl
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagem
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinationss
X
Ophthalmic assessmentt
X
Table revised per Amendment 02
Page 1149 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 102 of 168
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AChEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = International Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time, TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days, plus an additional window of up to 
30 days if required (revised per Amendment 02).  The interval between availability of the results of the last screening 
assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as possible and ideally should not 
exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur no more than 10 days after completion of the Baseline 
visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is required to take Exclusion 
Criterion No.20 into account (revised per Amendment 02).  Thus, the total Prerandomization Phase may be up to 60 days, 
plus an additional window of up to 30 days if required (revised per Amendment 02).
a:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  For any active infection within the last 4 weeks prior to randomization, the timing of randomization 
can be extended (up to 4 weeks) to allow the infection to resolve; psychometric tests (eg, MMSE, CDR) and safety 
laboratory tests conducted at Visit 2 must be repeated.  (revised per Amendment 02)
b:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
c:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
d:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  At 
the Screening Visit, the recommended order of assessments is: MMSE, ISLT (immediate recall), CBB, ISLT 
(delayed recall), CBB (repeat CBB for additional practice), CDR, and FAQ. The CBB may be repeated multiple times 
if required for the subject to pass completion and integrity criteria.  At the Baseline Visit, the assessments are to be 
conducted in the following order:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT 
(delayed recall). (revised per Amendment 02) At visits where the CDR or FAQ are conducted, the investigator will 
determine whether the caregiver or informant must attend in person or whether telephone contact will be suitable, and 
will base this determination upon the functional ability of the subject among other factors.
e:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
f:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
g:
Lymphocyte subsets to be measured include CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), 
CD16/CD56 (natural killer cells) and CD14 (macrophages).  Regulatory T cells will also be measured (CD4, CD25,
FoxP3).  Viability staining may also be employed.  Whenever unscheduled lymphocyte subset tests are performed or 
whenever scheduled lymphocyte subsets are repeated, a CBC with differentials, must also be repeated.  (revised per 
Amendment 02)
h:
Igs to be analyzed include IgG, IgA and IgM.
i:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
j:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine and free thyroxine.
k:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
Page 1150 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 103 of 168
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
assessments in the same imaging session. (revised per Amendment 01)
l:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.  An historical amyloid positive PET scan may be used if conducted within the 
previous 12 months and provided that the scan and result are considered acceptable by the central PET reading group.  
(revised per Amendment 02)
m:
For subjects who consent to CSF sample collection:  CSF will be collected by LP after fasting (preferred), or at least 
2 hours after the most recent meal.  A gravity drip collection method must be used.  Subjects will be encouraged to 
stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed at a similar time of day (±1 hour) for each 
individual subject. If the LP and cognitive tests are performed on the same day, the LP must be performed after the 
cognitive tests have been completed and the subject should rest and drink some fluid to hydrate before the LP.  The 
CSF sample will be used for PK and PD assessments.  A CSF sample will also be stored for testing in the event that 
the subject develops treatment-emergent adverse events that warrant further investigation (eg, treatment-emergent 
infection). (revised per Amendments 01 and 02)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops treatment-emergent adverse events that 
warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether 
the subject already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurological examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 1151 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 104 of 168
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological assessment via 
photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for lymphocyte subset
analysesl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for Igsm
X
X
X
X
X
X
X
X
X
X
Blood samples for isolation of PBMCs 
X
X
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample for storage for immune statuso
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 1152 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 105 of 168
Table 7 Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and exploratory 
biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 1153 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 106 of 168
Notes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled.
a:
Visit 3 should be conducted no more than 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless 
additional time is required to take Exclusion Criterion #20 into account.  (revised per Amendment 02)  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A 
window of ±10 days will be permitted for Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit 
windows, every effort should be made to bring the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20, respectively).  Subjects who discontinue study drug prematurely will also be 
scheduled to return to the study site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these visits have 
not already been performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB, and ISLT) will be conducted.   Regularly scheduled 
clinical efficacy visits do not need to be attended if they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days of either of the Follow-Up 
Visits (Visit 19 and Visit 20).  Subjects who discontinue early from study drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 2 posttreatment Follow-Up visits; 
one 4 weeks after the last dose of study drug and a second 12 weeks after the last dose of study drug (Visit 19 and Visit 20 respectively).  If clinically indicated, more frequent 
safety assessments can be made as UNS assessments or visits during the posttreatment Follow-Up period.  
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  Clinical biochemistry, urinalysis, CBC, 
lymphocyte subsets and Igs should always be performed at Visit 20, regardless of clinical significance at Visit 19.  (revised per Amendment 02)  
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern 
(eg, depigmentation, rash, herpetic lesion).
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets to be measured include CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and total 
Page 1154 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 107 of 168
lymphocytes.  Regulatory T cells will also be measured (CD4, CD25, and FoxP3). Viability staining may also be employed.  Whenever unscheduled lymphocyte subset tests 
are performed or whenever scheduled lymphocyte subsets are repeated, a Complete Blood Count, with differentials, must also be performed. (revised per Amendment 02)
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors. 
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within the 
7 days before Visits 14, 16, and 18 and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will be 
collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.  A PET scan will only be performed at Visit 18 or ED if the subject has a valid Screening PET scan for the purposes of 
longitudinal analyses; subjects who were determined to be eligible for the study on the basis of an historical PET scan will not have a PET scan performed at Visit 18 or ED  
(revised per Amendment 02)
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14 and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
For subjects who consent to CSF sample collection:  All visits at which CSF samples are scheduled to be taken also include blood PK and PD assessments and so the subject 
will be dosed at the clinic on these days. A CSF sample will be collected by LP between 4 and 8 hours postdose and at the same time of day as the subject's Baseline LP 
(±1 hour).  The CSF sample will be taken with the subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  If 
the LP and the cognitive tests are performed on the same day, the LP must be performed after the cognitive tests have been completed and the subject should rest and drink 
some fluid to hydrate before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical observation.  The CSF sample will not be taken at the 
ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the 
Page 1155 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 108 of 168
CSF sample will still be collected unless it was already collected within the past 3 months. (revised per Amendments 01and 02)
w:
Subjects reporting adverse events relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time as determined 
by the PI or Safety Physician for postdose medical observation.  (revised per Amendment 02)
Page 1156 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 109 of 168
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.1.1.1, and Figure 2.
See Section 9.5.1 for a full description of the procedures and assessments to be performed 
during this study.
Table 8
presents the number of blood and CSF samples, and the total volume of blood 
and CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline 
Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
18
2 x 5 mL
16 x 5 mL
90 mL
Lymphocyte subset analyses
18
2 x 4 mL
16 x 4 mL
72 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
9
2 x 2 mL
7 x 2 mL
18 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
322  mL
402  mL
CSF (For subjects who consent to CSF sample collection) (revised per Amendment 02)
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 1157 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 110 of 168
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the second follow-up visit (Visit 20).  In subjects who 
discontinue study drug early, but continue with efficacy assessments, SAEs only need to be 
solicited up to 3 months after the last dose of study drug.  However, any SAEs volunteered 
by subjects after this time point must be reported according to standard procedures.  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.
Page 1158 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 111 of 168
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Page 1159 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 112 of 168
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
Page 1160 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 113 of 168
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 4 and 12 weeks after the last dose of study drug 
(Visit 19 and Visit 20, respectively) (see Section 9.1.2.3).  See Table 7 for full details of the 
assessments to be performed at these visits.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when 
clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18, if 
these visits have not already been performed).  At these visits, only clinical efficacy 
assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  
Subjects who discontinue early from study drug are considered on study as long as they 
return for their regularly scheduled clinical efficacy visits as outlined above. Subjects who 
discontinue study drug early (as opposed to subjects whose dosing with study drug is 
temporarily suspended under Medical Monitor guidance) will not be permitted to restart 
study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
Page 1161 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 114 of 168
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
Page 1162 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 115 of 168
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  (revised per Amendment 02)

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects
(revised per Amendment 01)  
Page 1163 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 116 of 168
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendments 01 and 02)  
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD 
subjects as measured by vMRI

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in 
MCI/Prodromal and mild to moderate AD subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild to moderate AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal and 
mild moderate AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12, and
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by 
vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal 
and mild to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD 
subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol.  The PP Analysis Set will be used to conduct a 
sensitivity analysis of the primary efficacy endpoint.  Details of the evaluability 
criteria will be determined before database lock and treatment unblinding, and will be 
specified in the statistical analysis plan.
Page 1164 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 117 of 168

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement 
and at least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
Page 1165 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 118 of 168
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
WHO DD preferred term.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be defined as medications 
that (1) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (2) started on or after the date of the first dose of study drug up to the
date of the last dose.  All medications will be presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy Analyses
The MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  
Page 1166 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 119 of 168

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 
25% improvement over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
All mild to moderate AD subjects will be included in the efficacy evaluations of the Mild to 
Moderate AD cohort.  The analysis of the Mild to Moderate AD cohort is based on the group 
sequential design.  Interim analyses in the Mild to Moderate AD cohort will only be 
performed after the MCI/Prodromal cohort crosses the early success boundary.  The early 
efficacy signal based on the change from baseline of ADCOMS at 18 months is defined as 
crossing the interim-analysis boundaries for overwhelming efficacy in the mild to moderate 
AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha 
spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and 
final analyses, respectively, according to 2 planned interim analyses at the 60% and 
80% information fraction. (revised per Amendment 01)  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Page 1167 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 120 of 168
Sensitivity analysis of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the PP set and as such, no multiplicity adjustments will be 
made to account for the interim analyses.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoint:  (revised per 
Amendment 02)

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild to moderate AD.  If there is no treatment group-by-population interaction 
in the overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild to 
moderate AD) in the overall study.  Otherwise, the MMRM analysis will only include 
subjects in the Mild to Moderate AD cohort.  The comparison between placebo and active 
doses will be performed within mild to moderate AD subjects regardless of subjects included 
in the MMRM analysis.  Dunnett’s method will be used to control for multiplicity due to 
multiple comparisons.
Page 1168 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 121 of 168
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendments 01 and 02)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild to moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to 
moderate AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 
18 months in MCI/Prodromal and mild to moderate AD subjects.  Data from early 
discontinuations will also be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild to 
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 
18 months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD 
subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 
12 and 18 months in MCI/Prodromal and mild to moderate AD subjects
Page 1169 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 122 of 168
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual E2609 concentration listings.  The PK 
Analysis Set will be used for summaries of E2609 concentrations. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in CSF will 
be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  The PK/PD relationship between plasma PK parameters with other 
biomarkers may also be explored using similar methods.
Additionally, the relationship between plasma and CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between plasma and CSF exposure to E2609 
and the change from baseline for 18 months in the ADAS-cog, the CDR, and the MMSE,
will be explored graphically.  Any emergent relationship will be explored through population 
PK/PD modeling.
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
Page 1170 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 123 of 168
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum severity (mild, moderate, or severe).  The number (percentage) of subjects with 
Page 1171 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 124 of 168
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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with treatment-
related TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.
Page 1172 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 125 of 168
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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
Page 1173 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 126 of 168
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE, CDR, and CBB (see 
Section 9.7.1.6).
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Page 1174 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 127 of 168
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 
0.15 (SUVR), respectively; this would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per 
Amendment 01)  
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in Section 9.7.1.6.2.  
The statistical power was estimated through simulation for the dose-response assumption that 
the percent reduction in change from baseline of ADCOMS at 18 months compared with 
placebo would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated 
power for the actual planned 200 mild to moderate AD subjects is approximately 80% 
assuming a 2-sided alpha of 0.05.  (revised per Amendment 01)
9.7.3
Interim Analysis
An interim safety analysis will be conducted when the first 60 subjects have completed 
12 weeks of treatment (or discontinue study drug early) in Stage A. (revised per 
Amendment 01)  
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of 
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
Page 1175 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 128 of 168
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, including MCI/Prodromal subjects from 
Stage A and Stage B).  (revised per Amendment 01)  Further interim efficacy analyses will 
be conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
A group sequential design will be used for the Mild to Moderate AD cohort.  (revised per 
Amendment 01)  This design includes 3 looks, 2 interim looks (when 60% and 80% 
information fractions are achieved) and 1 final look.  The information fraction is the number 
of assessments in all treatment arms divided by the total number of expected assessments.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the 
first, second, and final analyses, respectively.  If the actual information fraction during the 
Page 1176 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 129 of 168
interim analyses is different from 60% or 80% at the interim, the efficacy boundaries will be 
adjusted based on the actual information fraction.  
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort 
based on the data for mild to moderate AD subjects available at that time. (revised per 
Amendment 01)  
Randomization into the Mild to Moderate AD cohort will remain at a fixed schedule 
throughout Stage B.  (revised per Amendment 01)  
The interim analyses in the Mild to Moderate AD cohort will be conducted by an
independent analysis group.  (revised per Amendment 01)  
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 
active doses for the first 100 MCI/Prodromal subjects randomized, including those 
randomized from both Stage A and Stage B).  Thereafter, randomization probabilities to each 
treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  (revised 
per Amendment 01)  
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)  
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 
dose groups (5, 15, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild to 
moderate AD subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 and 
50 mg E2609) at a 1:1:1 ratio. (revised per Amendment 01)  
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
Page 1177 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 130 of 168
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 1178 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 131 of 168
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology 
2007;68:1588-95.
Page 1179 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 132 of 168
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on 
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 1180 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 133 of 168
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex. 
Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 1181 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 134 of 168
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
25.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 1182 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 135 of 168
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan. The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 1183 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 136 of 168
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, 
ECGs, rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 1184 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 137 of 168
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 1185 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 138 of 168
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 CTA 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 CTA 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 CTA 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.
Page 1186 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 139 of 168
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.
Page 1187 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 140 of 168
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Male:
>44 – 3.0 x 44
Female:
>3.0 – 5.032
Male
>3.0 – 5.044
Female:
>5.0 – 20.032
Male:
>5.0 – 20.044
Female:
>20.032
Male:
>20.044
Page 1188 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 141 of 168
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Page 1189 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 142 of 168
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 1190 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 143 of 168
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and 
Listing 6.  Medications permitted with restrictions are listed in Listing 7, Listing 8, and 
Listing 9.  These may not be all-inclusive listings.  Please contact the medical monitor(s) if 
the investigators have any questions or concerns regarding any medication not listed that 
your subjects may be taking before enrollment or start during the course of the E2609-G000-
202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 9 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 1191 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 144 of 168
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Blaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Antinausea/ nausea
Page 1192 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 145 of 168
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 1193 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 146 of 168
Listing 2 Prohibited Medications Within 7 Days (or 5 Half-lives, Whichever is Longer) 
Before Randomization and Until after the Last Treatment Visit)
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Anticoagulants
Adeporin
Normiflo
Alteplase, tPA
Activase, Cathflo Activase
Anisindione
Miradon
Antithrombin III
ATryn, Thrombate III
Argatroban
Argatroban
Bivalirudin
Angiomax
Dabigatran
Pradaxa
Dalteparin
Fragmin
Danaparoid
Orgaran
Dicumarol
Dicumarol
Enoxaparin
Lovenox
Fondaparinux 
Arixtra
Heparin Sodium
Monoject
Lanoteplase
Lanoplase
Lepirudin
Refludan
Pentosan 
polysulfate sodium
Elmiron
Reteplase
Retavase, Retevase
Staphylokinase
Eskinase, Heberkinasa Kabikinase, Streptase, Thrombosolv, Zykinase
Streptokinase
Streptase
Tenecteplase
TNKase
Tinzaparin
Innohep
Urokinase
Abbokinase, Kinlytic
Warfarin
Coumadin, Jantoven
Antiplatelet drugs
Aspirin and Plavix 
(revised per 
Amendment 01)
For subjects who consent to CSF sample collection:  Aspirin or clopidogrel is permitted 
in all subjects.  Aspirin and clopidogrel in combination is not permitted.  (revised per 
Amendments 01 and 02)
For subjects who do not consent to CSF sample collection:  Aspirin and clopidogrel, 
individually or in combination, is permitted.  (revised per Amendment 02)
Page 1194 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 147 of 168
Note:  This list is not exhaustive.
Page 1195 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 148 of 168
Listing 3 Prohibited Medications Within 5 Half Lives or 60 Days, Whichever is 
Longer, Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
Page 1196 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 149 of 168
Listing 4 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 1197 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 150 of 168
Listing 5 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 1198 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 151 of 168
Listing 6 Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 1199 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 152 of 168
Permitted Prior/Concomitant Medications
Listing 7
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Follow-Up Visit 2
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 1200 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 153 of 168
Listing 8
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph 
SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
PRN = Pro re nata
Page 1201 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 154 of 168
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 8.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 1202 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 155 of 168
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine 
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone 
Risperdal
Thioridazine 
Mellaril
Thiothixene 
Navane
Trifluoperazine 
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Flunitrazepam
Rohypnol
Page 1203 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 156 of 168
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Flurazepam
Dalmane
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 1204 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 157 of 168
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
Page 1205 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 158 of 168
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
Page 1206 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 159 of 168
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 1207 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 160 of 168
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Relaxed
Page 1208 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 161 of 168
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Increased well-being
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Page 1209 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 162 of 168
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 1210 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 163 of 168
Appendix 5
Eisai Lymphocyte Subset Criteria for Study E2609-
G000-202:  Justification for a Population-Adjusted 
Approach
Introduction:
The Eisai clinical study, E2609-G000-202, requires the analysis of absolute numbers of 
various functional subsets of circulating lymphocytes. 
These are distinguished by 
identification of various complementary differentiation (CD) markers on the cell surface 
using fluorescent-labeled antibody reagents and flow cytometry. Current enumeration of 
certain lymphocyte subsets form part of the immunologically based eligibility criteria for 
study enrollment, as well as being monitored for safety for enrolled and treatment 
randomized subjects.  The Trucount™ M (Becton, Dickinson and Company [BD], BD 
Biosciences, San Jose, CA) antibody reagents used for the lymphocyte subset eligibility 
criteria, provides readouts for both absolute (BD Trucount tubes) and percentage of 
lymphocyte subsets, and includes the following CD markers: CD3 (T cells), CD4 (T helper 
cells), CD8 (cytotoxic T cells), CD16/56 (natural killer cells), CD14 (macrophages), and 
CD19 (B cells). 
Trucount lymphocyte subset reference ranges provided by the reagent manufacturer (BD) for 
both absolute and percentages were established for clinical use as an in vitro diagnostic using 
standardized reference interval methodology. These LLN for the various lymphocyte subsets 
are currently being used by the central laboratory for Eisai Study E2609-G000-202 to 
determine eligibility of screened subjects and as part of safety assessments during post-
randomization visits. The eligibility criterion excludes subjects with absolute counts of T and 
B cell markers (CD4, CD8, and CD19 respectively) less than the reference range lower limit 
of normal (<LLN) at Screening or Baseline. 
Need to assign age appropriate reference ranges:
Reference ranges established by the vendor according to working group guidance(3) may not 
be representative of different subgroup analyses (eg, ancestry, disease state, age, gender, 
etc.), and therefore interval adjustment may be required depending on the subpopulation of 
interest. The working group guidance for reference intervals (CLSI, 2010(4)) recommends 
examining data to determine if >10% of subjects are outliers (ie, more than 10% < LLN), and 
if so, to initiate development of subgroup-appropriate intervals by analyzing data from the 
literature or internal studies representing the reference population [a minimum of 
120 observations recommended by the guidance.(3)]
Data from the ongoing Study E2609-G000-202 has been examined and greater than 10% of 
the study population screening samples fall below the manufacturer recommended LLN for 
the key lymphocyte subsets. The population for Study E2609-G000-202 are patients aged 
50 to 85 years old inclusive with Mild Cognitive Impairment due to AD or with Mild to 
Moderate dementia due to AD.  Lymphocyte subset data from a data cut of 93 screened 
subjects was analyzed and showed that both CD8 and CD4 had greater than 10% of the 
Page 1211 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 164 of 168
subjects with results <LLN (26.9%, <220 cells/mm3 and 13%, <404 cells/mm3
, respectively); 
CD19 had approximately 10% of the subjects with results <LLN (9.7%, <80 cells/mm3). 
To further determine if the outlier data observations from the ongoing Study E2609-G000-
202 were associated with disease status or age, lymphocyte subset data from additional Eisai 
studies that included healthy elderly subjects or patients diagnosed with MCI or
mild/moderate AD were examined. The individuals from all 3 studies included the same 
50-to 85-year-old age range as the current E2609-G000-202 study. The studies evaluated 
include:  (1) Study E2609-A001-002 treatment study (n=50 healthy elderly); (2) Lymphocyte 
subset pilot study in healthy elderly [n=30]; and (3) Lymphocyte subset pilot study in 
AD/MCI [n=31].  Screening or baseline sample from all 4 studies had >10% of the  CD8 
absolute counts below reference LLN, 2 out of 4 had >10% of the CD19 absolute counts 
below reference LLN and 1 out of 4 had >10% of the CD4 absolute counts out of reference 
LLN [Table 10, Table 11, and Table 12]. The data suggests that the reference values of LLN 
for CD4, CD8, and CD19 subsets are not a disease-associated observation but are related to 
the age of the study population being evaluated.  
In addition to the Eisai study data, age related decline in lymphocyte subsets has been 
described in the literature Yan et.al.(1)(2) Analysis was performed using flow cytometry on 
peripheral blood leukocytes using healthy subjects across the 3rd and 10th decades of life. 
The results from the Yan study (n=80; 37 males, 43 females) demonstrated that with 
advancing age there was a significant decline in the percentage of lymphocytes, specifically 
naive T cells [CD3 P=0.03], cytotoxic T cells [CD8 P=0.08] and activated B cells 
[CD20/CD69 P=0.03] with certain subsets demonstrating even greater decline in males.(1)
The age associated changes in immune capabilities, termed “immunosenescence”, which 
include degenerative changes in the lymph nodes, effects on lymphocyte subsets and changes 
in adaptive immunity may underlie the increased risk of infection and cancer and decreased 
immune function in the elderly.  This, along with the data from the four Eisai studies 
described earlier, support the readjustment of the LLNs for the CD reference ranges used for 
eligibility in Study E2609-G000-202 such that they are better suited to the older patient 
population enrolling in this study which is thought to be representative of the wider patient 
population.  
Determining the new LLN criteria: 
The recommended method for establishing reference intervals is the nonparametric approach 
where the underlying distribution of the data does not matter.  The values received from the 
data (a minimum of 120 observations representing the subgroup population of interest is 
recommended) are rank ordered and can be used to evaluate the comparative reference 
interval.(3)    
When data from the 4 Eisai studies are put in rank order (see Table 10, Table 11, and Table
12), and a 10% cut value is applied to each of the 3 CD markers of interest the following 
age-adjusted LLN values are generated: 
Page 1212 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 165 of 168
Table 9
Summary of CD4, CD8, and CD19 LLNs and Age-Adjusted LLNs
Lymphocyte Subset
Current LLN
Age-adjusted LLN
CD4 absolute count
404 cells/mm3
396 cells/mm3
CD8 absolute count
220 cells/mm3
157 cells/mm3
CD19 absolute count
80 cells/mm3
74 cells/mm3
Table 10
Summary of CD Counts (Parameter: CD19)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
30
203
   Mean
213.47
198.49
159.20
172.77
192.57
   Median
189.66
163.00
118.50
159.50
164.86
   5th percentile
84.81
59.00
38.00
69.00
59.00
   10th percentile
102.26
81.00
42.00
70.50
74.00
   25th percentile
139.66
104.00
75.00
100.00
104.58
   75th percentile
261.51
225.00
225.00
246.00
246.00
   95th percentile
376.67
443.00
424.00
384.00
402.00
   Range
66.19, 
593.48
17.00, 
1066.00
37.00, 
455.00
39.00, 
415.00
17.00, 
1066.00
Table 11
Summary of CD Counts (Parameter: CD8)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
362.72
352.18
324.63
427.74
362.20
   Median
364.74
330.00
344.00
315.00
336.39     
   5th percentile
115.02
138.00
86.00
100.00
115.02     
   10th percentile
170.24
151.00
159.50
153.00
157.00     
   25th percentile
253.37
213.00
204.00
217.00
230.00     
   75th percentile
465.52
425.00
405.00
494.00
438.00     
   95th percentile
614.57
716.00
557.00
988.00
702.00     
   Range
98.45, 
702.50
37.00, 
803.00
61.00, 
702.00
54.00, 
2255.00
37.00, 
2255.00   
Page 1213 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 166 of 168
Table 12
Summary of CD Counts (Parameter: CD4)
BEAM 002
BEAM 202 Pilot AD/MCI
Pilot 
Control
Combined 
Total
   n
50
93
30
31
204        
   Mean
846.15
839.58
789.27
804.52
828.46     
   Median
836.94
805.00
777.50
771.00
791.50     
   5th percentile
388.44
337.00
395.00
351.00
344.00     
   10th percentile
479.55
361.00
490.00
427.00
396.00     
   25th percentile
639.54
620.00
661.00
669.00
633.77     
   75th percentile
1031.49
1078.00
924.00
1014.00
1039.50    
   95th percentile
1315.55
1404.00
1124.00
1327.00
1347.00    
   Range
274.90, 
1643.55
197.00, 
1481.00
248.00, 
1720.00 
143.00, 
1336.00
143.00, 
1720.00    
References:
1. Yan et al., Immunity and Ageing 2010 v. 7:4; The effect of ageing on human 
lymphocyte subsets: comparison of males and females.
2. Wikby et al., Biogerontology 2008 vol 9: 299; The immune risk profile is associated 
with age and gender: findings from three Swedish population studies of individuals 
20-100 years of age.
3. Horowitz eJIFCC 2008 vol. 19 (2) Reference intervals: practical aspects).  
4. Horowitz et al., CLSI Vol 28 no. 30 Clinical and Laboratory Standards Institute’s 
(CLSI) newly revised document Defining, Establishing, and Verifying 
Reference Intervals in the Clinical Laboratory; Approved Guideline—Third 
Edition (C28-A3), published in November 2010 EP28-AC3
Page 1214 of 1658


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 167 of 168
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product 
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 1215 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
(Amendment 02)
E2609-G000-202
Eisai
FINAL (v4.0):  05 Nov 2015
Confidential
Page 168 of 168
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof-of-Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 1216 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page i of viii
REVISION HISTORY
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion to allow for 
enrollment of mild to moderate 
AD subjects in Stage A and 
expand the Stage B mild AD
cohort to also include moderate 
AD subjects
To collect safety data in a wider 
range of AD patients.

Title Page

Synopsis –
o
Objectives
o
Study Design
o
Number of Subjects
o
Inclusion/Exclusion Criteria
o
Study Treatments
o
Efficacy Assessments
o
Study Endpoints
o
Efficacy Analyses
o
Interim Analyses
o
Adaptive Randomization 
o
Sample Size

Section 5.3

Section 7

Section 8 (and all subsections)

Section 9.1, Section 9.1.1

Figure 1

Section 9.2.1, Section 9.2.2, Section 9.2.3

Section 9.2.5.3 and Section 9.2.5.4

Section 9.3, Section 9.3.1, Section 9.3.2

Section 9.4.1, Section 9.4.3, Section 9.4.4

Section 9.5.1.3.1

Section 9.7.1.1.2, Section 9.7.1.1.3

Section9.7.1.4

Section 9.7.1.6, Section 9.7.1.6.2, 
Section 9.7.1.6.3

Section 9.7.1.8.2

Section 9.7.2.2

Section 9.7.3

Section 9.7.4
Revised inclusion criteria for 
MMSE to ≥16 from ≥20
The MMSE score is used as a 
cut-off for the most impaired 
subject that would be eligible 
for the study.  Lowering the 
MMSE inclusion from ≥20 to 
≥16 is consistent with 
expanding the Mild AD cohort 
to a Mild to Moderate AD 
cohort.

Synopsis – Inclusion/Exclusion Criteria

Section 9.3.1
Page 1217 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page ii of viii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Revised inclusion criteria for 
FAQ to ≤24 from ≤20
As for the MMSE, the FAQ 
score is used as a cut-off for the 
most impaired subject that 
would be eligible for the study.  
Revising the FAQ inclusion 
from ≤20 to ≤24 is consistent 
with expanding the Mild AD 
cohort to a Mild to Moderate 
AD cohort, and is consistent 
with an MMSE inclusion of 
≥16.

Synopsis – Inclusion/Exclusion Criteria

Section 9.3.1
Revised exclusion criteria such 
that small arachnoid cysts are 
not necessarily exclusionary 
Arachnoid cysts are a common 
finding in otherwise healthy 
subjects.  Small lesions (<1 cm 
in diameter) are generally not 
considered clinically significant 
and if discovered incidentally 
no long term follow up is 
routinely required.

Synopsis – Inclusion/Exclusion Criteria

Section 9.3.2
Revised exclusion criteria for Ig 
(IgG, IgA, or IgM) to specify
that levels below the LLN at 
Screening or Baseline need not 
be exclusionary
For subjects with a Screening 
or Baseline IG level <LLN to 
be considered for continuation 
in the study, assessment of 
clinical significance of the 
finding will be required.  A 
finding of "not clinically 
significant" must be agreed 
between the Investigator and 
Medical Monitor in order for 
the subject to continue in the 
study.

Synopsis – Inclusion/Exclusion Criteria

Section 9.3.2
Revised text to provide 
instructions for subject assent 
and associated consent by a 
legal representative  for subjects 
who the Investigator considers 
not to have the capacity to 
consent themselves
With the expansion of the 
patient population to include 
moderately demented subjects 
it was necessary to provide 
directions regarding the 
consenting process for subjects 
considered to be lacking the 
capacity to consent themselves.

Section 5.3
Revised number of clinical sites 
to 30 from 25
For feasibility purposes.

Synopsis – Sites

Section 6

Section 9.1

Section 9.3
Added allowance for Tier 1 and
Tier 2 screening assessments to 
be performed on the same day
Added to provide operational 
clarity for the sites.

Section 9.1.1.1

Table 6
Page 1218 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page iii of viii
Revisions to Version 2.0
New version/date: Version 3.0, 28 May 2015
Change
Rationale
Affected Protocol Sections
Removed requirements for 
MRIs to include sequences for 
resting state functional MRI
This was an error and should 
not have been included in the 
original protocol.

Table 6

Table 7
Revised text to clarify that on 
visits where CSF collection 
takes place, the CSF collection 
need not take place on the same 
day as the cognitive testing for 
that visit
Added to provide operational 
clarity for the sites.

Section 9.5.1.4.2

Table 6

Table 7
Revised text to clarify that the 
most important efficacy 
assessment to keep blinded 
from safety data is the CDR.
Added to provide operational 
clarity for the sites.

Synopsis – Safety Assessments

Section 9.4.6

Section 9.5.1.5
Revised text to allow PK blood 
sample and PD blood samples 
to be taken either shortly before 
or shortly after the LP on CSF 
days
Added to provide operational 
flexibility for the sites.

Section 9.5.1.4.1

Section 9.5.1.4.2

Table 6

Table 7
Revised Sponsors Grading for 
Laboratory Values for the 
following analytes:  
lymphocytes, neutrophils, 
albumin, creatinine, phosphate, 
and potassium serum-high 
(hyperkalemia)
Corrections made to align with 
the values for grading used by 
the central clinical laboratory 
for this study.

Appendix 1
Revised details regarding 
prohibited antiplatelet drugs 
Previous version incorrectly 
referenced a biomarker 
subgroup.  All subjects in this 
study will need to provide CSF 
samples.

Appendix 2; Listing 2
Revised grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency.
Throughout protocol
Page 1219 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page iv of viii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis - Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5.1 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis – Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis – Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
Inclusion/Exclusion  Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and 
International Normalized Ratio
(INR) to screening and baseline 
procedures
Screen for hepatic impairment

Synopsis –
Inclusion/Exclusion Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
For subjects who discontinue study 
drug prematurely, conduct efficacy 
To facilitate efficacy analyses, 
which are based on longitudinal 

Synopsis –Study Design 

Section 9.1.2.2

Section 9.3.3
Page 1220 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page v of viii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
modeling for all subjects

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol. The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis - Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis - Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addition of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis – Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline,
during treatment, and posttreatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis - Assessments,

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 

Synopsis - Concomitant 
Drug/Therapy

Section 7.1
Page 1221 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page vi of viii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
plasma levels of E2609

Section 9.4.7

Appendix 2(Listing 6)
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis – Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis – Analysis of 
Primary Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis – Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (excl criterion 8) but a blood 
draw for Vit B12 was inadvertently 
missed out of Table 6 in protocol 
version 1.

Synopsis – Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible 

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5.1
Page 1222 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page vii of viii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis – Study Endpoints

Section 9.7.1.2
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.6

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Page 1223 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page viii of viii
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 1224 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 1 of 146
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-
of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and 
Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to 
Alzheimer’s Disease (Prodromal Alzheimer’s Disease) and Mild to 
Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
V3.0
28 May 2015 (per Amendment 01)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
Page 1225 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 2 of 146
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-
4-fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, 
Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild to Moderate Dementia Due to Alzheimer’s Disease (revised per 
Amendment 01)
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 30 sites, United States only (revised per Amendment 01)
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  Approximately 42 months from initiation of Stage B (revised per Amendment 01)
Phase 2
Objectives
Primary Objectives
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/ Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol)
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
Mild to Moderate Dementia due to Alzheimer's Disease (referred to as mild to moderate 
AD throughout the protocol) (revised per Amendment 01)
Secondary Objectives
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI)
Page 1226 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 3 of 146
2. To evaluate the effect of E2609 compared with placebo on amyloid β(1-x) (Aβ[1-x]) in 
cerebrospinal fluid (CSF) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at
18 months in mild to moderate AD subjects (revised per Amendment 01)
Exploratory Objectives
(revised per Amendment 01)
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in 
CSF after 4 weeks and 18 months of treatment in mild to moderate AD subjects
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during post-treatment follow-up, in 
MCI/Prodromal and mild to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF β-amyloid converting enzyme 1 (BACE1)
measurements during 18 months of treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment and during 
post-treatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
7. To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and 
mild to moderate AD subjects, and to examine the effect of intrinsic and extrinsic factors 
(including N-acetyltransferase 2 [NAT2] phenotype) on the PK 
Page 1227 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 4 of 146
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild to moderate AD subjects
Study Design
This will be a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  A common 
set of inclusion criteria, consistent with the National Institute on Aging – Alzheimer’s 
Association (NIA-AA) clinical research criteria for Mild Cognitive Impairment (MCI) due to 
Alzheimer’s Disease (AD) or mild to moderate AD, will be required for all subjects.  In 
addition, the MCI due to AD population will also be consistent with the research criterion for 
“Prodromal AD” in that episodic memory will be impaired on a list learning task (ISLT).  As 
the non-demented subjects will be consistent with the criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild to moderate AD will be based on both clinical and 
biological (ie, confirmation of amyloid load in the brain) criteria.  (revised per 
Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (after the first 
60 randomized subjects have completed 12 weeks of treatment or have discontinued study 
drug early) before expanding enrollment to include a larger number of subjects in Stage B.  
(revised per Amendment 01) All MCI/Prodromal subjects will be included in the primary 
efficacy evaluation irrespective of whether they were recruited during Stage A or Stage B.  
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort only 
during Stage B.  All mild to moderate AD subjects will be included in the efficacy 
evaluations for that cohort.  (revised per Amendment 01)
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  
The Prerandomization Phase (up to 60 days) includes a Screening Visit (Visit 1) and a 
Baseline Visit (Visit 2).  All screening assessments (within 4 distinct tiers) must be 
completed, and eligibility to continue in the study confirmed, before any baseline 
assessments commence.  Following successful completion of the Prerandomization Phase, 
eligible subjects will be randomized and will enter the Randomization Phase, which will 
consist of 2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
Stage A
Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 4 treatment groups within 
each of the 2 clinical populations.  (revised per Amendment 01) In addition to the placebo 
group, 3 E2609 doses will be used to reduce CSF amyloid β levels by approximately 25%
(5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at steady state.  
PK/pharmacodynamic (PD) modeling has shown that these doses should achieve these 
targets when administered once daily (QD) with food, and these doses will be confirmed or 
adjusted based on the 4-week assessment of CSF Aβ(1-x).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Page 1228 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 5 of 146
Stage A, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  The DSMB will make 
recommendations to Eisai after each review as to whether any change(s) to the study are 
necessary.  Unless the DSMB recommends otherwise, randomization of subjects into 
Stage A will continue until 60 subjects have been randomized and dosed.  (revised per 
Amendment 01)
After 60 subjects in Stage A have completed 4 weeks of treatment, an interim analysis of the 
E2609 PK and PD profiles will be used to confirm the E2609 doses to be used for Stage B.
(revised per Amendment 01)  If the 95% confidence interval of the mean percentage change 
from baseline in CSF Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 
does not include its intended target value (ie, 25%, 50% and 75% reductions from baseline,
respectively for E2609 at 5 mg, 15 mg, and 50 mg QD), PK/PD modeling will be conducted.  
From this model, the new target plasma steady state concentrations of E2609 required to 
achieve the target levels of CSF Aβ(1-x) reduction will be estimated again.  Dose adjustment 
for Stage B may be considered if it is possible to get closer to the new target plasma steady 
state concentrations of E2609 required to achieve the intended target levels of CSF Aβ(1-x) 
reduction than is possible with the initially planned doses, given the limitation that E2609 
dose adjustments will have to be in 5-mg increments or decrements.  Subjects already 
randomized to a dose that needs to be adjusted will be switched to the new adjusted dose and 
complete their treatment at this new dose.
Once 60 subjects in Stage A have completed at least 12 weeks of treatment (or discontinued 
study drug early) an interim safety analysis will be conducted by Eisai and the DSMB. 
(revised per Amendment 01) Subjects in Stage A will continue study drug while the DSMB 
reviews all the available safety data, but randomization of additional subjects will not take 
place (ie, recruitment into Stage B will not commence) until the safety analysis is completed 
by the DSMB.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol.  Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are confirmed.  
Stage B will enroll, randomize, and dose additional eligible subjects up to a maximum of 500 
MCI/Prodromal and up to a maximum of 200 mild to moderate AD. The final total number 
of MCI/Prodromal subjects will depend upon whether the prespecified criteria for either 
early success or futility are met. (revised per Amendment 01) Safety data from Stage B will 
continue to be reviewed by the DSMB (approximately every 3 months) until recruitment to 
the study is completed; following this the DSMB will meet approximately every 6 months.  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD) whereas the Mild to Moderate 
AD cohort will only include 2 doses of E2609 (15 mg and 50 mg QD).  (revised per 
Amendment 01)
Page 1229 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 6 of 146
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort only 
during Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence 
according to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) 
until a total of 100 MCI/Prodromal subjects (including those from Stage A) have been 
randomized.  (revised per Amendment 01)   The remaining subjects in the MCI/Prodromal 
cohort in Stage B will then be randomized according to response adaptive randomizations 
based on the ADCOMS results using the Bayesian interim efficacy analyses.  The mild to 
moderate AD subjects will be randomized according to a fixed schedule (1:1:1 placebo; 15 
mg E2609; 50 mg E2609) throughout Stage B. (revised per Amendment 01)
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who 
discontinue study drug prematurely will also be scheduled to return to the study site for each 
scheduled visit when clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 
15, 16, 17, and 18) if these visits have not already been performed.  At these visits, only the 
clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be 
conducted.  Subjects who discontinue early from study drug are considered on study as long 
as they return for their regularly scheduled clinical efficacy visits as outlined above.
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
Number of Subjects

Stage A:  Approximately 250 MCI/Prodromal or mild to moderate AD subjects will 
be screened to provide 60 randomized subjects (target of 15 subjects per treatment 
arm).  There will be no limit to the number of subjects randomized from either 
clinical cohort.  (revised per Amendment 01)

Stage B:  Up to approximately 2100 MCI/Prodromal subjects will be screened to 
provide up to 500 randomized subjects.  The final number of MCI/Prodromal 
subjects will depend upon whether the prespecified criteria for either early success 
or futility are met.  In addition, up to approximately 835 subjects with mild to 
moderate AD will be screened to provide up to 200 randomized mild to moderate 
AD subjects.  The final number of mild to moderate AD subjects randomized in 
Stage B will depend upon the number of mild to moderate AD subjects previously 
randomized during Stage A. (revised per Amendment 01)
Page 1230 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 7 of 146
Inclusion Criteria
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD 
dementia and is "staged" or classified as either MCI or mild to moderate dementia  and 
also complies with the following: (revised per Amendment 01)
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16  (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading 
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects 
can be entered into the study but there should be no plans to initiate treatment with 
AChEIs or memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization.
Exclusion Criteria
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or magnetic resonance imaging (MRI)
2. Modified Hachinski Ischemic Scale >4 
Page 1231 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 8 of 146
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as arachnoid cysts and < 1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors (eg, 
meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild to moderate AD diagnosis or 
could interfere with study assessments or procedures (revised per Amendment 01)
7. A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the lower limit of normal 
(LLN) for the testing laboratory) at Screening
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to lumbar puncture for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
(including subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
Page 1232 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 9 of 146
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR) must be repeated.
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings. 
(revised per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate electrocardiograms 
(ECGs).  A history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, 
family history of long QT Syndrome) or the use of concomitant medications that prolong 
the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
Page 1233 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 10 of 146
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years 
before Screening, current use of recreational drugs or a positive urine drug test at 
Screening.  Subjects who test positive in the urine drug screen need not be excluded if in 
the clinical opinion of the investigator, this is due to the subject taking prior/concomitant 
medications for a medical condition that is not exclusionary and not due to drug abuse.
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal 
ideation questions 4 or 5, or any suicidal behavior assessment within 6 months before 
Screening, at Screening, or at the Baseline Visit; or has been hospitalized or treated for 
suicidal behavior in the past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications 
section of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can 
be undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, 
or to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
Page 1234 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 11 of 146
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period 
and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 
days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they 
are postmenopausal [amenorrheic for at least 12 consecutive months, in the 
appropriate age group, and without other known or suspected cause] or have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
or for 28 days after study drug discontinuation.
Study Treatments
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets to 
match E2609 will be of identical appearance.  Each subject will receive 2 tablets, which
when combined will make up the required doses of E2609 (see below) or placebo, to be 
administered orally QD with food.  

Stage A:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or placebo (revised per 
Amendment 01)

Stage B, MCI/Prodromal Cohort:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or 
placebo (revised per Amendment 01)

Stage B, Mild to Moderate AD Cohort:  2 doses (15 mg and 50 mg) of E2609 or 
placebo.  (revised per Amendment 01)
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 
2 years, comprising: 

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days
(In subjects who have an active infection within 4 weeks of the planned 
randomization date, the duration of the pre-randomization phase can be extended by 
up to 4 weeks to allow additional time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Page 1235 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 12 of 146
Concomitant Drug/Therapy
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit (see Appendix 2 for a 
detailed listing of these agents):  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-
lives or 7 days (whichever is longer) before randomization

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-
lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization

Live vaccines are not permitted within 3 months before randomization.  This does 
not apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before 
randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which 
are central nervous system (CNS) active and may affect cognitive function, are 
not permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if, in the 
opinion of the investigator, this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
Page 1236 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 13 of 146
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of 
selected items (12 total) from 3 fully validated and well established clinical tools, the 
ADAS-cog (4 items), the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should 
be administered in full in the morning, or, if not possible, consistently at the same time of 
day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be 
used since it is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery: A computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test.  Speed of response is the measure.
2. Identification – a simple choice reaction time test.  Speed of response is the measure.
3. One Card Back – a simple working memory test.  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test.  Accuracy of response is the 
measure.
International Shopping List Task: The ISLT is a verbal learning and episodic memory test 
assessing both immediate and delayed recall.  
Functional Assessment Questionnaire: The FAQ has 10 items concerned with performing 
daily tasks necessary for independent living.  Either a caregiver or informant or the subject 
provides performance ratings on 10 complex activities of daily living performed within the 
preceding 4 weeks.  
Volumetric Magnetic Resonance Imaging: 
vMRI will be used to evaluate disease 
modification, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed depending on emerging 
data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic and Other Biomarker Assessments
Brain atrophy will be measured by vMRI: see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), total tau (t-tau), and p-tau will be measured in 
CSF.  BACE1 levels and activity in CSF will also be measured.  Other exploratory 
biomarkers (eg, miRNA) may also be evaluated in plasma and/or CSF.
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Page 1237 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 14 of 146
Baseline Period have amyloid deposition in the brain. Longitudinal amyloid PET imaging 
will also be conducted after 18 months of treatment (or at ED, providing the subject has 
received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging will only be 
conducted through to the time at which acceptable 18-month PET scans have been obtained 
for at least 25 subjects per treatment arm for each amyloid PET ligand used.
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4
homozygous or heterozygous status versus non-carriers and NAT2 status will be used in the 
statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA 
sequence variability on the absorption, distribution, metabolism, and elimination of E2609, 
development of AEs, as well as the underlying AD.  Variations in E2609 exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR. (revised per Amendment 01) Routine safety 
assessments will include the monitoring and recording all AEs and SAEs, monitoring of 
hematology, blood chemistry, and urinalysis, measurement of vital signs, regular ECGs, 
physical and neurological examinations, and centralized dermatological assessments (via 
photography) at regular intervals.  AEs that might indicate signals of possible drug abuse 
potential will require a more detailed follow-up.  Subjects reporting AEs relating to abnormal 
dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these 
events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be 
measured (by a centralized laboratory) every week for the first month, every 2 weeks for the 
next 2 months (Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  
Thereafter they will be monitored every 3 months until the end of the Treatment Period and 
at both Follow-Up Visits.  Serum IgG, IgA, and IgM will be monitored monthly for the first 
3 months, at 6, 12, and 18 months, and at both Follow-Up Visits.  
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, 
and posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at baseline and at 3-month intervals during the Treatment Period.  
These assessments will specifically include evaluation of any areas of depigmentation or 
rash.  Subjects will also be questioned by the investigator at each visit to identify any 
changes that might represent a drug-induced rash/reaction or infection.  Subjects and their 
caregivers/ informants will be instructed to contact the investigator if they see any lesions or 
other symptoms that might be associated with a drug-induced rash/reaction or infection, so 
such AEs can be reviewed promptly.  
Baseline and on-study blood, DNA, and CSF samples will be taken and stored from all 
subjects.  These samples may be tested for exploratory biomarkers associated with study 
drug or disease, or in the event that a subject develops AEs that warrant further investigation
Page 1238 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 15 of 146
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected 
infective agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months
during the Treatment Period and at the final Follow-Up Visit.  Additional safety MRI scans 
are to be performed as clinically necessary.  MRI acquisition and interpretation will be 
organized centrally to ensure reproducibility and consistency between units involved.  
Full neurological examinations will be performed at Baseline, at 6, 12, and 18 months, and at 
both Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  The neurological examinations will
include muscle strength testing and assessment of cranial nerves including olfaction as well 
as other parts of the CNS.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline 
and at regular intervals throughout the Treatment and Follow-Up Periods.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. 
An additional examination will be conducted if the subject experiences visual disturbances 
during the course of the study.
A number of safety-related criteria for discontinuation of study drug are specified for the 
study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid 
chromatography method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based 
enzyme-linked immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF 
Aβ(1-42), tau, and p-tau will be performed using ELISAs.
BACE1 levels and activity may be measured using a customized assay.  Substrates of 
BACE1 inhibition may also be explored using Western blots or other amenable methodology 
if clinical observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
Page 1239 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 16 of 146
Secondary Endpoints
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects

The derived ADCOMS at 18 months of treatment in mild to moderate AD 
subjects  (revised per Amendment 01)
Exploratory Endpoints
(revised per Amendment 01)
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate 
AD subjects as measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild to 
moderate AD subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months: ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal 
and mild to moderate AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of 
treatment in MCI/Prodromal and mild to moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal 
and mild to moderate AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 
and, 18 months in MCI/Prodromal and mild to moderate AD subjects as measured 
by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in 
MCI/Prodromal and mild to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and 
extrinsic factors (including NAT2 phenotype) in MCI/Prodromal and mild to 
moderate AD subjects
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of 
study drug and have at least 1 postdose safety assessment.
Page 1240 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 17 of 146

The Full Analysis Set (FAS) is the group of randomized subjects who receive at 
least 1 dose of study drug and have baseline and at least 1 postdose primary 
efficacy measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD 
measurement and at least 1 posttreatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian 
adaptive design.  Frequent interim analyses will be performed to assess the probability of 
early success and futility and to make early stopping decisions.  Response adaptive 
randomization will be used to update the randomization probability among treatment groups 
at each interim analysis.  Key definitions relevant to the Bayesian aspects of the adaptive 
design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before
full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01): All mild to moderate AD 
subjects will be included in the efficacy evaluations of the Mild to Moderate AD cohort.  
The analysis of the Mild to Moderate AD cohort is based on the group sequential design.  
Interim analyses in the Mild to Moderate AD cohort will only be performed after the 
Page 1241 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 18 of 146
MCI/Prodromal cohort crosses the early success boundary.  The early efficacy signal based 
on the change from baseline of ADCOMS at 18 months is defined as crossing the 
interim-analysis boundaries for overwhelming efficacy in the mild to moderate AD 
population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha spending 
function will be used to assess overwhelming efficacy.  The corresponding OF boundaries 
based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and final analyses, 
respectively, according to 2 planned interim analyses at the 60% and 80% information 
fraction. (revised per Amendment 01)
Analysis for the primary endpoint 
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, CDR, CBB, ISLT, 
and FAQ), subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Sensitivity analyses of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis. This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
Page 1242 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 19 of 146
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the per protocol set, and as such, no multiplicity adjustments 
will be made to account for the interim analyses.  In case of early success, the conventional 
analyses will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild to moderate AD. If there is no treatment group-by-population interaction 
in the overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild to 
moderate AD) in the overall study.  Otherwise, the MMRM analysis will only include 
subjects in the Mild to Moderate AD cohort.  The comparison between placebo and active 
doses will be performed within mild to moderate AD subjects regardless of subjects included 
in the MMRM analysis.  Dunnett’s method will be used to control for multiplicity due to 
multiple comparisons. (revised per Amendment 01)
Analysis for exploratory endpoints
(revised per Amendment 01)
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild to moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to 
moderate AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 
months in mild to moderate AD subjects.  Data from early discontinuations will also 
be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild to moderate AD subjects
Page 1243 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 20 of 146

Change from baseline in left and right hippocampal, whole brain, and total 
ventricular volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal 
and mild to moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 
months in MCI/Prodromal and mild to moderate AD subjects 

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD 
subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 
12 and 18 months in MCI/Prodromal and mild to moderate AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.  Summary statistics for CSF biomarkers will be assessed for evidence of a dose 
relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in plasma and 
CSF will be explored graphically and any emergent relationship will be explored through 
population PK/PD modeling.  Additionally, the relationship between CSF exposure to E2609 
and the derived ADCOMS at 18 months, and the relationship between CSF exposure to 
E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  Any emergent relationships will be explored through 
population PK/PD modeling.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  Further information is in the “Pharmacodynamic, 
Pharmacogenomic, 
and 
Other 
Biomarker 
Assessments” 
section. 
 
Details 
of 
pharmacogenomic testing may be provided and reported separately.
Page 1244 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 21 of 146
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  Serum IgG, IgM, IgA will be measured and summarized in the same 
manner as other laboratory parameters.
Interim Analyses
An interim safety analysis will be conducted when the first 60 subjects have completed 
12 weeks of treatment (or discontinue study drug early) in Stage A. (revised per 
Amendment 01)
The MCI/Prodromal Cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be 
conducted by an independent committee that has expertise with Bayesian adaptive design in 
clinical studies.  An unblinded external independent analysis group will provide the interim 
analysis outcomes to the committee at each interim analysis.  The committee will ensure the 
integrity of the interim analysis and response adaptive randomization process through review 
of efficacy data.  In addition, the committee will act in an independent advisory capacity to 
monitor the Bayesian interim analysis outcomes according to the early success and futility 
boundaries prespecified in the protocol.  The committee will not be charged with any subject 
safety issues; this will remain the responsibility of the DSMB.  The DSMB will continue to 
monitor the safety aspects of the study throughout Stage A and Stage B.  The study may be 
stopped for safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, including MCI/Prodromal subjects from 
both Stage A and Stage B).  (revised per Amendment 01) Further interim efficacy analyses 
will be conducted after each additional 50 MCI/Prodromal subjects have been randomized, 
up to a maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 
450, 500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
200 subjects’ interim analysis, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.  
Page 1245 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 22 of 146
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The Mild to Moderate AD Cohort (revised per Amendment 01)
A group sequential design will be used for the Mild to Moderate AD cohort.  This design 
includes 3 looks, 2 interim looks (when 60% and 80% information fractions are achieved) 
and 1 final look.  Interim analyses will be performed after the MCI/Prodromal cohort crosses 
the early success boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 
0.0423 for the first, second, and final analyses, respectively.  If the actual information 
fraction during the interim analyses is different from 60% or 80% at the interim, the efficacy 
boundaries will be adjusted based on the actual information fraction.  If early success in the 
MCI/Prodromal cohort is not achieved before the final analysis that is performed when all 
subjects have completed 18 months treatment, then only a final analysis will be performed in 
mild to moderate AD subjects.  In the event of futility in the MCI/Prodromal cohort, an 
analysis will be performed for the Mild to Moderate AD cohort based on the data for mild to 
moderate AD subjects available at that time.  (revised per Amendment 01)
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 
active doses for the first 100 MCI/Prodromal subjects randomized, including  those 
randomized from both Stage A and Stage B).  Thereafter, randomization probabilities to each 
treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  (revised 
per Amendment 01)
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 
dose groups (5 mg, 15 mg, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild 
to moderate AD subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 mg 
and 50 mg E2609) at a 1:1:1 ratio. (revised per Amendment 01)
Page 1246 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 23 of 146
Stratification (revised per Amendment 01)
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by 
means of simulations.  Extensive study simulations have shown that a total of 500 subjects 
will be sufficient to demonstrate that the most likely ED90 dose achieves a 25% improvement 
over placebo with a probability of at least 80% in the interim and final analyses.  There is at 
least a 90% probability of study success for the dose response scenarios where treatment was 
considered to have a clinically meaningful treatment effect.  Simulations have also shown 
that if there is no obvious dose effect, the probability of falsely claiming superiority to 
placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects 
per group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  
There are 3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false (1-sided).  The null hypotheses will be tested using 
Dunnett’s method with 1-sided alpha of 0.05.  The statistical power was estimated through 
simulation for a moderate dose-response assumption that the percent reduction in change 
from baseline of total hippocampal volume compared with placebo would be 15%, 20%, and 
25% corresponding to the 3 doses, respectively.  The estimated power for actual planned 
study sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  
Under a stronger dose-response assumption (ie, the percent reduction in change from 
baseline of total hippocampal volume compared with placebo is twice as much as that in the 
moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those
for vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, 
a common SD of change from baseline was estimated at 0.33 and a reasonable mean 
difference between treatment and placebo was estimated as 0.25 (standardized uptake value 
ratio [SUVR]).  Assuming a moderate dose-response, the best dose would achieve a 
difference of 0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 
and 0.15 (SUVR), respectively, it would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per Amendment 01)
ADCOMS at Month 18: The null hypothesis is that there is no difference between active 
dose and placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The 
alternative hypothesis is that at least 1 null hypothesis is false.  The null hypotheses will be 
tested using Dunnett’s test with 2-sided alpha of 0.05 as described for the Mild to Moderate 
Page 1247 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 24 of 146
AD cohort in the secondary analysis section.  The statistical power was estimated through 
simulation for the dose-response assumption that the percent reduction in change from 
baseline of ADCOMS at 18 months compared with placebo would be 33% and 50% 
corresponding to the 2 doses, respectively.  The estimated power for the actual planned 200 
mild to moderate AD subjects is approximately 80% assuming a 2-sided alpha of 0.05.
(revised per Amendment 01)
Page 1248 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 25 of 146
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................25
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................30
5
ETHICS............................................................................................................................33
5.1
Institutional Review Boards/Independent Ethics Committees ..............................33
5.2
Ethical Conduct of the Study.................................................................................33
5.3
Subject Information and Informed Consent...........................................................34
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................36
7
INTRODUCTION ...........................................................................................................37
7.1
Nonclinical and Clinical Safety Data.....................................................................38
8
STUDY OBJECTIVES....................................................................................................41
8.1
Primary Objectives.................................................................................................41
8.2
Secondary Objectives.............................................................................................41
8.3
Exploratory Objectives ..........................................................................................41
9
INVESTIGATIONAL PLAN..........................................................................................43
9.1
Overall Study Design and Plan..............................................................................43
9.1.1
Prerandomization Phase...............................................................................46
9.1.1.1
Screening Period..................................................................................46
9.1.1.2
Baseline Period ....................................................................................48
9.1.2
Randomization Phase...................................................................................48
9.1.2.1
Treatment Period..................................................................................48
9.1.2.2
Early Discontinuation ..........................................................................49
9.1.2.3
Follow-up Period .................................................................................49
9.2
Discussion of Study Design, Including Choice of Control Groups.......................50
9.2.1
Overview......................................................................................................50
9.2.2
Rationale for Study Population....................................................................51
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................51
9.2.4
Rationale for Clinical Endpoints..................................................................52
9.2.5
Rationale for Biomarkers.............................................................................53
9.2.5.1
Overall Rationale .................................................................................53
9.2.5.2
Soluble Biomarkers in CSF .................................................................54
9.2.5.3
Amyloid PET .......................................................................................54
9.2.5.4
vMRI....................................................................................................55
9.2.6
Clinical Risks and Mitigation Strategy........................................................55
Page 1249 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 26 of 146
9.3
Selection of Study Population................................................................................57
9.3.1
Inclusion Criteria .........................................................................................57
9.3.2
Exclusion Criteria ........................................................................................58
9.3.3
Removal of Subjects from Therapy or Assessment.....................................62
9.4
Treatments..............................................................................................................65
9.4.1
Treatments Administered.............................................................................65
9.4.2
Identity of Investigational Product...............................................................66
9.4.2.1
Chemical Name and Formula of E2609...............................................66
9.4.2.2
Comparator Drug .................................................................................66
9.4.2.3
Labeling for Study Drug......................................................................66
9.4.2.4
Storage Conditions...............................................................................67
9.4.3
Method of Assigning Subjects to Treatment Groups...................................67
9.4.4
Selection of Doses in the Study...................................................................67
9.4.5
Selection and Timing of Dose for Each Subject..........................................69
9.4.6
Blinding........................................................................................................69
9.4.7
Prior and Concomitant Therapy...................................................................70
9.4.8
Treatment Compliance.................................................................................71
9.4.9
Drug Supplies and Accountability...............................................................71
9.5
Study Assessments.................................................................................................73
9.5.1
Assessments.................................................................................................73
9.5.1.1
Demography.........................................................................................73
9.5.1.2
Baseline Assessments ..........................................................................73
9.5.1.2.1
Medical History and Physical Examinations.................................73
9.5.1.2.2
Viral Testing ..................................................................................74
9.5.1.2.3
B12 Testing....................................................................................74
9.5.1.2.4
TB Exposure Testing .....................................................................74
9.5.1.2.5
Urine Drug Testing ........................................................................74
9.5.1.3
Efficacy Assessments...........................................................................74
9.5.1.3.1
Psychometric Assessments ............................................................74
9.5.1.3.2
Volumetric MRI.............................................................................75
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................76
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................76
9.5.1.4.1
Pharmacokinetic Assessments .......................................................76
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................77
9.5.1.5
Safety Assessments..............................................................................78
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..79
Page 1250 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 27 of 146
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................82
9.5.1.5.3
Laboratory Measurements .............................................................83
9.5.1.5.4
Vital Signs and Weight Measurements..........................................84
9.5.1.5.5
Physical Examinations...................................................................84
9.5.1.5.6
Electrocardiograms ........................................................................84
9.5.1.5.7
Safety MRI.....................................................................................85
9.5.1.5.8
Dermatological Assessment...........................................................86
9.5.1.5.9
Neurological Examination .............................................................86
9.5.1.5.10
Pregnancy Test...............................................................................86
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................87
9.5.1.5.12
Biomarker Samples........................................................................87
9.5.1.5.13
Ophthalmic Examinations..............................................................87
9.5.2
Schedule of Procedures/Assessments ..........................................................87
9.5.2.1
Schedule of Procedures/Assessments ..................................................87
9.5.2.2
Description of Procedures/Assessments Schedule...............................95
9.5.3
Appropriateness of Measurements...............................................................96
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................96
9.5.4.1
Reporting of Serious Adverse Events..................................................96
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................97
9.5.4.3
Reporting of Events Associated with Special Situations.....................97
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................97
9.5.4.3.2
Reporting of Study-Specific Events...............................................98
9.5.4.4
Expedited Reporting ............................................................................98
9.5.4.5
Breaking the Blind...............................................................................98
9.5.4.6
Regulatory Reporting of Adverse Events ............................................99
9.5.5
Completion/Discontinuation of Subjects.....................................................99
9.5.6
Abuse or Diversion of Study Drug ............................................................100
9.5.7
Confirmation of Medical Care by Another Physician ...............................100
9.6
Data Quality Assurance .......................................................................................100
9.6.1
Data Collection ..........................................................................................100
9.6.2
Clinical Data Management ........................................................................101
9.7
Statistical Methods...............................................................................................101
9.7.1
Statistical and Analytical Plans..................................................................101
9.7.1.1
Study Endpoints.................................................................................101
Page 1251 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 28 of 146
9.7.1.1.1
Primary Endpoint.........................................................................101
9.7.1.1.2
Secondary Endpoints ...................................................................101
9.7.1.1.3
Exploratory Endpoints .................................................................102
9.7.1.2
Definitions of Analysis Sets...............................................................102
9.7.1.3
Subject Disposition............................................................................103
9.7.1.4
Demographic and Other Baseline Characteristics .............................103
9.7.1.5
Prior and Concomitant Therapy.........................................................104
9.7.1.6
Efficacy Analyses ..............................................................................104
9.7.1.6.1
Primary Efficacy Analysis...........................................................105
9.7.1.6.2
Secondary Efficacy Analyses ......................................................106
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................107
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................108
9.7.1.7.1
Pharmacokinetic Analyses...........................................................108
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................108
9.7.1.8
Safety Analyses..................................................................................109
9.7.1.8.1
Extent of Exposure.......................................................................109
9.7.1.8.2
Adverse Events ............................................................................109
9.7.1.8.3
Laboratory Values........................................................................110
9.7.1.8.4
Vital Signs....................................................................................111
9.7.1.8.5
Electrocardiograms ......................................................................111
9.7.1.8.6
Other Safety Analyses..................................................................112
9.7.2
Determination of Sample Size ...................................................................112
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................112
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort 
(revised per Amendment 01) .............................................................113
9.7.3
Interim Analysis.........................................................................................113
9.7.4
Other Statistical/Analytical Issues .............................................................115
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................115
10
REFERENCE LIST .......................................................................................................116
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....120
11.1
Changes to the Protocol .......................................................................................120
11.2
Adherence to the Protocol....................................................................................120
11.3
Monitoring Procedures.........................................................................................120
11.4
Recording of Data................................................................................................121
11.5
Identification of Source Data...............................................................................121
11.6
Retention of Records............................................................................................122
Page 1252 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 29 of 146
11.7
Auditing Procedures and Inspection....................................................................122
11.8
Handling of Study Drug.......................................................................................122
11.9
Publication of Results ..........................................................................................123
11.10 Disclosure and Confidentiality ............................................................................123
11.11 Discontinuation of Study .....................................................................................123
11.12 Subject Insurance and Indemnity.........................................................................123
12
APPENDICES ...............................................................................................................124
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................63
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................64
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................68
Table 4
Clinical Laboratory Tests...........................................................................83
Table 5
Lymphocyte Subtyping..............................................................................84
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................88
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................91
Table 8
Summary of Blood and CSF Sample Volumes..........................................95
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202.............................................................44
Figure 2
Assessments to be Performed at Screening by Tier...................................47
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................124
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........126
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 139
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................142
Page 1253 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 30 of 146
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg 1-
42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carobxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
Page 1254 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 31 of 146
Abbreviation
Term
ED
early discontinuation
ED90
lowest effective dose that achieves 90% of the greatest treatment effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild to 
moderate AD
mild to moderate dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
MMSE
Mini Mental State Examination
Page 1255 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 32 of 146
Abbreviation
Term
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OF
O’Brien-Fleming 
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Page 1256 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 33 of 146
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR)
regarding clinical studies, including Part 50 and Part 56 concerning informed subject
consent and IRB regulations and applicable sections of US 21 CFR Part 312
Page 1257 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 34 of 146

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for 
studies conducted within any European Union country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
understand it or if the identified caregiver or informant is unable to read, an impartial witness 
should be present during the entire informed consent discussion. If, in the Investigator's 
opinion, a subject lacks capacity to consent, the subject's assent should be obtained in 
addition to the written informed consent of a legal representative (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local 
laws and regulations).  (revised per Amendment 01) After the ICF and any other written 
information to be provided to subjects is read and explained to the subject and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
Page 1258 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 35 of 146
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
Page 1259 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 36 of 146
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 125 investigational sites globally (30 sites in the United States for 
Stage A and 125 sites globally for Stage B). (revised per Amendment 01)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 1260 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 37 of 146
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010, Lu, et 
al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, thus 
accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild to 
moderate AD dementia are stages on a single disease spectrum, which follows an 
Alzheimer’s pathological cascade.  (revised per Amendment 01) Recent consensus papers 
from the international workgroups of the National Institute on Aging-Alzheimer’s 
Association (NIA-AA), have endorsed this hypothesis (Albert, et al., 2011; Jack, et al., 2011; 
McKhann, et al., 2011; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild to moderate dementia due to Alzheimer’s Disease (referred to as mild to moderate AD
throughout the protocol) to determine whether the effects of E2609 in this later stage 
population are comparable with those established in the MCI/Prodromal population within 
Page 1261 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 38 of 146
this same study. (revised per Amendment 01)  In the MCI/Prodromal population, Bayesian 
response adaptive randomization design is used with frequent interim analyses to continually 
update randomization allocation based on emerging clinical endpoint data.  This approach 
allows for ongoing assessment of drug futility or evidence of early success and can mitigate 
the risks associated with larger and longer studies required to demonstrate clinical efficacy 
by leading to more efficient study termination or early advancement to a Phase 3 program.  
Results from this study will guide both the decision to move into Phase 3 development and 
the selection of the dose strengths to be taken into Phase 3.  Moreover, this study is intended 
to be supportive for registration in the MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5 mg, 15 mg and 50 mg) administered once daily (QD) for 18 months.  In the mild to 
moderate AD population, this study will compare placebo and 2 oral doses of E2609 (15 mg 
and 50 mg) administered QD for 18 months.  To date, the longest duration of dosing with 
E2609 is 14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  
(revised per Amendment 01)  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the first 60 randomized subjects have completed 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  The study also includes a 
number of exclusion criteria, specific blinded safety monitoring procedures and safety 
criteria for discontinuation of study drug in light of the preclinical and clinical safety data 
collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50 mg dose only, aged 65 to 
85 years).  
Page 1262 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 39 of 146
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
14 days of dosing so as to assess the pharmacokinetic (PK) levels of E2609 and the 
pharmacodynamic (PD) effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
Page 1263 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 40 of 146
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 1264 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 41 of 146
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild to moderate AD (revised per Amendment 01)  
8.2
Secondary Objectives
The secondary objectives are:  
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the effect of E2609 compared with placebo on Aβ(1-x) in CSF after 4 weeks 
and 18 months of treatment in MCI/Prodromal subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild to moderate AD subjects (revised per Amendment 01)  
8.3
Exploratory Objectives
(revised per Amendment 01)  
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild to moderate AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild to moderate AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after 4 weeks and 18 months of treatment in mild to moderate AD subjects
Page 1265 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 42 of 146
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, in 
MCI/Prodromal and mild to moderate AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b. The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d. The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild to moderate AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
posttreatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
7. To characterize the population PK of E2609 in MCI/Prodromal and mild to moderate AD 
subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild to moderate AD subjects
Page 1266 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 43 of 146
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study 202 is a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild to moderate AD.  (revised 
per Amendment 01)
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild to moderate AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the non-
demented subjects will be consistent with criteria for both MCI due to AD and Prodromal 
AD they will be identified as MCI/Prodromal subjects in this protocol. The diagnosis of 
MCI/Prodromal AD or mild to moderate AD will be based on both clinical and biological (ie, 
confirmation of amyloid load in the brain) criteria.  (revised per Amendment 01)
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) before expanding enrollment to include a larger number of subjects in Stage B. .  
All MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective 
of whether they were recruited into Stage A or Stage B.  Bayesian response adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B. All mild to 
moderate AD subjects will be included in the efficacy evaluation of that cohort. (revised per 
Amendment 01)  
Both Stage A and Stage B will consist of 2 phases: Prerandomization and Randomization.  
The Prerandomization Phase (up to 60 days) will consist of a Screening Visit and a Baseline 
Visit.  Screening assessments will be organized into 4 tiers; see Section 9.5.2.2, Table 6, and
Figure 2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
In Stage A, all subjects (MCI/Prodromal and mild to moderate AD) will be randomized 
1:1:1:1 to 4 treatment groups (E2609 at 3 doses or placebo).  In Stage B, randomization of 
MCI/Prodromal subjects will start off at a 1:1:1:1 ratio (E2609 at 3 doses or placebo), until a 
total of 100 MCI/Prodromal subjects have been randomized.  Remaining subjects in the 
MCI/Prodromal cohort will be randomized according to response adaptive randomizations 
based on the ADCOMS results using the Bayesian interim efficacy analyses.  Subjects with 
mild to moderate AD who are recruited in Stage B will be randomized in a 1:1:1 ratio to 3 
treatment groups (E2609 at 2 doses or placebo). (revised per Amendment 01)  
An overview of the study design is presented in Figure 1.
Page 1267 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 44 of 146
Figure 1
Design of Study E2609-G000-202
(revised per Amendment 01 )
R = randomization.
Page 1268 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 45 of 146
Stage A
Stage A will be limited to approximately 30 sites in the United States.  (revised per 
Amendment 01) Stage A will randomize 60 eligible subjects at Visit 3, 1:1:1:1 to 4 treatment 
groups within each clinical cohort.  (revised per Amendment 01)  There will be no Bayesian 
adaptation during Stage A.  In addition to the placebo group, 3 doses of E2609 will be used
to reduce CSF Aβ levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg)
from baseline, respectively, at steady state.  PK/PD modeling shows these doses should 
achieve these targets when administered QD with food and will be confirmed or adjusted 
based on the 4-week assessment of CSF Aβ(1-x) (see Section 9.4.4).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A, an independent DSMB (including at least 1 immunologist) will review all safety 
data in an unblinded manner.  The DSMB will make recommendations to Eisai after each 
review as to whether any change(s) to the study are necessary.  Unless the DSMB 
recommends otherwise, randomization of subjects into Stage A will continue until 60 
subjects have been randomized and dosed.  (revised per Amendment 01)  
After 60 subjects in Stage A have completed 4 weeks of treatment, an interim analysis of the 
E2609 PK and PD profiles will be used to confirm the E2609 doses to be used for Stage B 
(see Section 9.4.4).  (revised per Amendment 01)  
Once 60 subjects in Stage A have completed at least 12 weeks of treatment (or discontinued 
study drug early) an interim safety analysis will be conducted by Eisai and the DSMB.  
(revised per Amendment 01)  Subjects in Stage A will continue study drug while the DSMB 
reviews all the available safety data, but randomization of additional subjects will not take 
place (ie, recruitment into Stage B will not commence) until the safety analysis is completed 
by the DSMB.  At the time of this interim safety analysis, some subjects will have more than 
12 weeks of safety data.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol. Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are confirmed.  
Based on data from Stage A, the protocol will be reviewed and may be amended before 
beginning Stage B.  Safety data from Stage B will continue to be reviewed by the DSMB
(approximately every 3 months) until recruitment in the study is completed; following this 
the DSMB will meet approximately every 6 months.
Stage B will be conducted globally and will enroll, randomize, and dose additional eligible 
subjects up to a maximum of 500 MCI/Prodromal subjects and up to a maximum of 200 mild 
Page 1269 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 46 of 146
to moderate AD subjects. The final total number of MCI/Prodromal subjects will depend 
upon whether the prespecified criteria for either early success or futility are met.  (revised 
per Amendment 01)  
In Stage B, both cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD), whereas the Mild to Moderate 
AD cohort will only include 2 doses of E2609 (15 mg and 50 mg QD).  (revised per 
Amendment 01)  
Bayesian response adaptive randomization will be used in the MCI/Prodromal cohort during 
Stage B.  Randomization of MCI/Prodromal subjects into Stage B will commence according 
to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) until a total of 
100 MCI/Prodromal subjects (including those from Stage A) have been randomized.  
(revised per Amendment 01)  The remaining subjects in the MCI/Prodromal cohort in Stage 
B will then be randomized according to response adaptive randomizations based on the 
ADCOMS results using the Bayesian interim efficacy analyses.  The mild to moderate AD 
subjects will be randomized according to a fixed schedule (1:1:1 placebo; 15 mg E2609; 50 
mg E2609) throughout Stage B. (revised per Amendment 01)  
Interim efficacy analyses are planned and are discussed in Section 9.7.3.
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days and a window of 7 to 10 days is to be 
observed between the completion of all Baseline Visit assessments and randomization into 
the study at Visit 3.  Thus, the Prerandomization Phase will last for up to 60 days.  The series 
of assessments conducted during this phase will determine eligibility for randomization into 
the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization the clinician will provide a judgment on the classification of a subject as either 
MCI/Prodromal or likely mild to moderate AD.  (revised per Amendment 01)  This judgment
may be discussed and reviewed with the Sponsor or Sponsor’s representative, as necessary.
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Page 1270 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 47 of 146
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  Tier 2 procedures may be performed on the same day as Tier 1 procedures as 
long as the results of all Tier 1 procedures (eg, delayed recall on the ISLT) show that the 
subject is eligible to continue with screening activities. (revised per Amendment 01)
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) 
at Screening.  The investigator will determine whether the caregiver or informant must attend in person or whether 
Page 1271 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 48 of 146
telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other 
factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days.
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination will be 
performed.  A urine pregnancy test will be conducted for females of childbearing potential.  
Blood will be collected from all subjects for clinical chemistry and hematology, lymphocyte 
subset analyses, Ig analyses, and PD assessments.  Blood samples will be collected and 
stored for determination of a subject’s previous exposure to infective pathogens in the event 
of AEs that warrant further investigation occurring at a later point in the study.  Psychometric 
assessments will be administered to the subject in the order stated in Table 6.  The caregiver 
or informant needs to be present at this visit.  The Columbia Suicide Severity Rating Scale 
(C-SSRS) will also be administered (Section 9.5.1.5.11).
CSF will be obtained at this visit for PK and PD assessments (see Section 9.5.1.5.3).  
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase within 7 to 10 days following completion of the Baseline Visit 
assessments.
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
Page 1272 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 49 of 146
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
9.1.2.3
Follow-up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and is projected to end by Oct 2019 (end date 
will depend on actual recruitment rate).

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
Page 1273 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 50 of 146
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The 2 stage design of the study allows for the safety and tolerability of E2609 to be assessed 
in a limited number of subjects (n=60) before expanding recruitment into a larger population 
of subjects. (revised per Amendment 01)  
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild to 
moderate AD to determine whether the effects of E2609 in this later stage population are 
comparable with those established in the MCI/Prodromal population within this same study
(see Section 9.2.3 for discussion of the Bayesian design used in this study). (revised per 
Amendment 01)  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of well 
established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (see Section 9.2.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; an amyloid 
biomarker, which is the change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months 
of treatment in MCI/Prodromal subjects; and a cognitive and functional assessment, which is 
the change from baseline in the derived ADCOMS at 18 months of treatment in mild to 
moderate AD subjects.  (revised per Amendment 01)  Exploratory endpoints including 
assessments of efficacy, safety and other biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
Page 1274 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 51 of 146
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain is approaching a plateau and significant neurodegeneration has occurred (Jack, et 
al., 2010).  Consequently, there is a growing view within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  However, this hypothesis remains to be demonstrated with 
clinically effective therapies, and may not apply to all therapeutic classes, it is possible that 
this consideration explains the failure of the humanized monoclonal antibody bapineuzumab 
(which targeted brain amyloid) to demonstrate clinical efficacy in late-phase studies in mild-
to-moderate AD dementia.  (revised per Amendment 01)
With this consideration taken into account, the primary clinical population of focus in this 
study is subjects with MCI/Prodromal AD.  The mechanism of action of a BACE1 inhibitor 
where amyloid production is reduced means E2609 is more likely to be efficacious (ie, slow 
disease progression) the earlier in disease progression treatment is started, where limited 
neurodegeneration has occurred and associated clinical deficits are at a minimum.  However, 
since the effect of BACE1 inhibition along the AD continuum remains to be characterized, 
E2609 will also be evaluated for its profile in mild to moderate stages of AD, in the event 
data emerge supporting its use beyond MCI/Prodromal AD. Indeed, recent data support the 
notion of continued progression of amyloid pathology even in these later stages of the disease 
(Hu, et al., 2015), although at a slower pace, suggesting a positive effect of BACE inhibition 
and amyloid beta reduction cannot be ruled out even in the later stages of the disease 
trajectory.  Hence, in this study, E2609 will be assessed in subjects with disease states 
ranging from MCI/Prodromal to mild and even moderate AD.  (revised per Amendment 01)  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with more advanced disease such as
mild to moderate AD.  (revised per Amendment 01)  For example, a study of tarenflurbil, a 
selective Aβ(1-42)-lowering agent, on cognition and function in subjects with mild to 
moderate AD showed the subjects with mild AD had lower rates of decline than those in the 
placebo group in activities of daily living and global function; however, slowing of cognitive 
decline did not differ significantly (Wilcock, et al., 2008).  Similarly, differential effects on 
cognitive measures have been observed with solanezumab, where some benefit from 
treatment was observed in subjects with mild AD, although studies with solanezumab were 
considered to have failed to improve cognition or functional ability significantly (Doody, et 
al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor E2609 in 2 
different subject populations that differ in terms of AD severity before the initiation of large 
Phase 3 clinical studies. (revised per Amendment 01)
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
Page 1275 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 52 of 146
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild to moderate AD will be assessed as a “nested” population that does not 
follow the Bayesian adaptive design.  It was not considered appropriate to have a Bayesian 
design for both cohorts as this would have substantially increased the overall study sample 
size, delayed analyses of dose response, and would have added background “noise” for the 
comparison of subjects with MCI/Prodromal AD compared with those with mild to moderate 
AD. Data from each cohort will be analyzed independently for the purposes of decision 
making.  A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild 
to moderate AD confounding the results for the primary population (MCI/prodromal).  
(revised per Amendment 01)  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
Page 1276 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 53 of 146
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility 
inclusion criterion)

To evaluate safety (principally by magnetic resonance imaging [MRI])

To confirm a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
amyloid PET and to establish that this PD effect is maintained long-term

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
Page 1277 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 54 of 146
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both total tau (t-tau) and p-tau are sensitive markers of axonal and neuronal degeneration 
(t-tau) and neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel 
with disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have 
been correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful 
predictors of cognitive decline and progression to dementia due to AD.  Rebalancing 
dysregulated amyloid production early in the process may positively affect the 
neurodegenerative process and thus affect these markers and benefit the disease trajectory.  
Therefore, monitoring these markers in conjunction with amyloid imaging may provide 
further supportive evidence of efficacy.  
Baseline levels of Aβ(1-42), tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be performed in this study for 2 primary reasons: 1) to confirm 
the presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild to 
moderate AD at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels 
in the brain, both by whole brain analysis (the average of 5 to 6 cortical regions) and brain 
region analysis. (revised per Amendment 01)
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted until 18-month PET scans of acceptable quality have been obtained for at 
least 25 subjects per treatment arm for each amyloid PET ligand used.
Page 1278 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 55 of 146
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the mild to moderate AD population).  (revised per Amendment 01) 
A large body of data has shown that structural MRI reliably tracks disease progression in 
AD.  Atrophy tends to occur preferentially in the lateral temporal and posterior parietal 
regions during the early stages of disease and progresses towards the anterior regions of the 
brain (frontal cortex) in its later stages.  Clinically efficacious doses are predicted to be 
associated with a slowing in the rate of hippocampal atrophy compared with rates observed 
in the placebo and non-efficacious dose groups.  Treatment effects on left and right 
hippocampal, whole brain, and total ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as those with mild AD-dementia.  Lower 
levels of CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF tau in 
addition to the presence of the ApoE4 allele have all been associated with greater rates of 
brain atrophy (Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in 
various analyses.  Hippocampal atrophy has also been shown to predict clinical progression
independently of amyloid levels in the brain (Jack, et al., 2010), and this measure will be 
entered as a covariate in the analysis of the clinical endpoints along with the aforementioned 
variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  
Page 1279 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 56 of 146

Two-stage study design:  there will be a pause in recruitment after 60 subjects have
been randomized to study drug (Stage A).  Only after the safety of E2609 in these 
first 60 subjects (consisting of up to 12 weeks data for the later subjects and longer 
dosing periods for the earlier subjects) has been reviewed by the DSMB and 
considered acceptable, will randomization of further subjects into the study 
commence (Stage B). (revised per Amendment 01)

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and 
percentage change from baseline), skin rash, reoccurrence of herpes virus infections 
including any oral herpes, genital herpes or shingles, other infections, MRI changes, 
ECGs, and pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course 
of the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of
vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will 
be questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and posttreatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood, DNA, and CSF samples will be taken and stored for all 
subjects.  These samples may be tested in the event that a subject develops AEs that 
warrant further investigation (eg, if a subject develops a treatment-emergent 
infection) (see Section 9.5.1.2.2).
Page 1280 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 57 of 146

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Treatment Period, and at the final Follow-Up Visit.

Full neurological examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  Details of the neurological 
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using 
the detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, 
Baseline, and at regular intervals during the Treatment and Follow-Up Period (see 
Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 2 off-treatment Follow-Up
visits (4 and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated.

An ophthalmic examination will be conducted at Baseline and if the subject 
experiences visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will randomize 60 eligible MCI/Prodromal or mild to moderate AD subjects at 
approximately 30 sitesin the United States.  There will be no restriction to the number of 
subjects from either population.  Stage B will randomize subjects at approximately 125 sites 
globally.  Recruitment will continue in Stage B until a maximum of approximately 500 
MCI/Prodromal subjects and up to a maximum of approximately 200 mild to moderate AD 
subjects have been randomized (including subjects randomized during Stage A).  The final 
total number of MCI/prodromal subjects will depend upon whether the prespecified criteria 
for either early success or futility are met.  The number of mild to moderate AD subjects 
randomized in Stage B will depend upon the number of mild to moderate AD subjects 
randomized during Stage A. (revised per Amendment 01)
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
or mild to moderate dementia  and also complies with the following: (revised per 
Amendment 01)    
Page 1281 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 58 of 146
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤24 (revised per Amendment 01)
d.
MMSE ≥16 (revised per Amendment 01)
2. Amyloid positive PET image based on centralized PET scan reading 
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitor (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
Page 1282 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 59 of 146
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (however, lesions diagnosed as  arachnoid cysts and < 1cm in 
diameter at their greatest diameter need not be exclusionary) or brain tumors (eg, 
meningioma). (revised per Amendment 01)
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild to moderate AD diagnosis or 
could interfere with study assessments or procedures (revised per Amendment 01)  
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
Page 1283 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 60 of 146
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR) must be repeated.
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
23. Ig (IgG, IgA, or IgM) levels below the LLN at Screening or Baseline, unless both the 
Investigator and the Medical Monitor agree that the finding is not clinically significant.  
The assessment of clinical significance will include, but not be limited to, evidence of 
clinical immunodeficiency.  The discussion with the Medical Monitor should include a 
detailed review of medical history of infections, clinical and laboratory findings.  (revised 
per Amendment 01)
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
Page 1284 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 61 of 146
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
Page 1285 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 62 of 146
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 
days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 28 days after study drug discontinuation.
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 4 and 12 weeks after the last dose of study drug (see Section 9.1.2.3).  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Page 1286 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 63 of 146
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4 (T 
helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation threshold 
will be set at below the level of the LLN, at a level that represents a greater risk of 
opportunistic infection in the treated population.  For CD4 (T helper cells) the 
discontinuation threshold is 250 cells/µL.  For CD8 (cytotoxic T cells) and CD19 (B 
cells) the discontinuation thresholds are 150 cells/µL and 50 cells/µL, respectively.  Any 
subject who has CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) 
absolute counts below the discontinuation threshold as confirmed by a repeat test 
conducted within 1 week of the initial test will be discontinued from study drug.
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the LLN and the discontinuation threshold will have lymphocyte subset
counts performed on a weekly basis.  Subjects with a >33% reduction from baseline in 
CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts will also 
have lymphocyte subset counts performed on a weekly basis.  For these subjects, the 
decision as to whether the subject remains on study drug or is to be discontinued from 
study drug will be based upon clinical judgment and will take into account any clinical 
presentation in addition to the lymphocyte subset counts.  These subjects may continue 
with treatment if there is no clinical evidence of infection.  They will be discontinued 
from study drug if they have infections of a moderate to severe intensity (eg, subjects 
whose infections are not localized, or are systemically unwell, or who require systemic 
antiinfective drug treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue or 
discontinue
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
discontinuation threshold
Retest within 1 week
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
discontinue study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts between LLN and 
discontinuation threshold or >33% reduction from 
baseline in CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts
Lymphocyte subset counts to be 
performed weekly until counts 
return to ≥ LLN or no more 
than 33% reduction from 
baseline
Decision will be based upon 
lymphocyte subset counts and 
clinical judgment
LLN = lower limit of normal.
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
Page 1287 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 64 of 146
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the LLN and the discontinuation thresholds 
or have shown >33% reduction from baseline, subjects with infections of moderate 
intensity will be discontinued from study drug (eg, subjects whose infections are not 
localized, or subjects who are systemically unwell, or who require systemic antiinfective 
drug treatment).  All subjects with infection who are discontinued from study drug will 
be followed for a period of 12 weeks or until the infection resolves/ stabilizes or until the 
CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have 
returned to >LLN (whichever comes latest).
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
Mild
Moderate
Severe
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
discontinuation threshold
Discontinue
study drug
Discontinue
study drug
Discontinue
study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or 
CD19 (B cells) absolute counts between LLN and 
discontinuation threshold or >33% reduction from 
baseline in CD4 (T helper cells), CD8 (cytotoxic 
T cells), or CD19 (B cells) absolute counts
May continue 
treatment with study 
drug unless 
clinically indicated
Discontinue
study drug
Discontinue
study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts always >LLN and 
no reduction from baseline >33%
May continue 
treatment with study 
drug unless 
clinically indicated
May continue 
treatment with study 
drug unless clinically 
indicated 
(See (e) for exception)
Discontinue
study drug
LLN = lower limit of normal.
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 4 and 12 weeks after the last dose of 
study drug.  They will also undertake an Unscheduled Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
Page 1288 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 65 of 146
be performed at approximately the time of the second Follow-Up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  
Treatments to be administered in Stage A and Stage B are shown below and in Figure 1.The 
2 highest E2609 doses (15 mg and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A, will be used for the mild to moderate AD population in Stage B.
(revised per Amendment 01)  

Stage A:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or placebo

Stage B, MCI/Prodromal Cohort:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or 
placebo

Stage B, Mild to Moderate AD Cohort:  2 doses (15 mg and 50 mg) of E2609 or 
placebo. (revised per Amendment 01)  
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
Page 1289 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 66 of 146
9.4.2
Identity of Investigational Product
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5 mg, E2609 15 mg, E2609 50 mg, or 
placebo.  The tablets will be supplied by the Sponsor in labeled blister packs.  The product 
release certificates for E2609 and placebo will be included in the clinical study report for this 
protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
Page 1290 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 67 of 146
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for Stage A (all subjects), for Stage B MCI/Prodromal subjects and Stage B for mild to 
moderate AD subjects are described in Section 9.4.1. (revised per Amendment 01)  
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5 mg, 15 mg, and 50 mg QD administered as the tablet formulation with food in this 
study should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% 
at steady state, respectively (Table 3).
Page 1291 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 68 of 146
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1
Activity
% Reduction 
CSF A(1-x)
5
6.2
3.3
80.3
16.2
33
15
18.6
10
240.9
36.6
56
50
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = Beta-amyloid converting enzyme, CSF = cerebrospinal fluid,  Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013). Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and mild to moderate AD 
dementia patients. (revised per Amendment 01)
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 400 mg (17.3% 
decrease).  No subjects had infections or drug rash while receiving E2609 100 mg QD or at 
lower doses in Study 002, whereas at 200 mg and 400 mg QD, 4 subjects had symptomatic 
orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The highest dose 
for Study 202 of 50 mg QD (tablet administered with food) is therefore expected to have a 
similar or better safety profile compared with the 100 mg QD capsule (administered fasted) 
in Study 002.  Specific exclusion criteria, blinded and unblinded safety monitoring 
procedures, and safety criteria for discontinuation from study drug are included in this study
in order to mitigate any immunology-related risk with E2609, particularly in light of the 
progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
In Stage A, all subjects will be randomized to receive either placebo or E2609 at 5 mg, 15 
mg, or 50 mg QD.  In Stage B, subjects in the MCI/Prodromal cohort will continue to be 
randomized to receive either placebo or E2609 at 5 mg, 15 mg, or 50 mg QD. In Stage B,
subjects in the Mild to Moderate AD cohort will be randomized to receive either placebo or 
E2609 at 15 mg or 50 mg QD, but not the 5-mg QD dose.  The rationale for not including an 
E2609 5-mg QD dose in the dose regimens for Stage B subjects with mild to moderate AD is 
Page 1292 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 69 of 146
that more advanced disease may require greater reduction in CSF Aβ levels for comparable 
effects. (revised per Amendment 01)  
After 60 subjects in Stage A have completed 4 weeks of treatment, an interim analysis of the 
E2609 PK and PD profiles will be used to confirm the E2609 doses to be used for Stage B, 
where PD is measured as reductions from baseline in CSF Aβ(1-x) levels.  (revised per 
Amendment 01)  If the 95% confidence interval of the mean percentage change from 
baseline in CSF Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 does not 
include its intended target value (ie, 25%, 50%, and 75% reductions from baseline,
respectively for E2609 at 5 mg, 15 mg, and 50 mg), PK/PD modeling will be conducted.  
This PK/PD modeling will use the observed PK and PD data from Stage A and will relate the 
average steady state plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage 
reduction from baseline after 4 weeks of dosing.  From this model, the new target plasma 
steady state concentrations of E2609 required to achieve the target levels of CSF Aβ(1-x) 
reduction will be estimated again.  Dose adjustment for Stage B may be considered if it is 
possible to get closer to the new target plasma steady state concentrations of E2609 required 
to achieve the intended target levels of CSF Aβ(1-x) reduction than is possible with the 
initially planned doses, given the limitation that E2609 dose adjustments will have to be in 5-
mg increments or decrements.  Subjects already randomized to a dose that needs to be 
adjusted will be switched to the new adjusted dose and complete their treatment at this new 
dose.
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects and all personnel involved 
with the conduct and interpretation of the study, including investigators, site personnel, and 
Eisai staff will be blinded to the treatment codes (double-blind).  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (ie, those who are trained and certified to perform the 
various cognitive assessments that are undertaken in this study).  Furthermore, at the site, the 
notes and reports relating to safety assessments must be kept separate from the notes and 
reports relating to efficacy, particularly for the CDR. (revised per Amendment 01)
Page 1293 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 70 of 146
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
The PK/PD interim analysis to confirm the E2609 doses to be used for Stage B will be 
conducted by an independent group.  Any changes to dose will be reflected in an amendment 
to the protocol and the Statistical Analysis Plan will detail how data will be handled in the 
primary analysis.  
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and
Listing 6.  Medications that are permitted with restrictions are listed in Listing 7, Listing 8, 
and Listing 9.
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives 
or 7 days (whichever is longer) before randomization 

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-
lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization
Page 1294 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 71 of 146

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not 
permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Period.  
CRAs will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
Page 1295 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 72 of 146

Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of 
the principal investigator’s current medical license (required for United States sites) 
or medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, and (e) documentation of 
returns to the sponsor.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs 
and empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and, together with unused study drugs that were shipped to the site 
Page 1296 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 73 of 146
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
Page 1297 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 74 of 146
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT 
(immediate recall), CBB, and ISLT (delayed recall) at Screening; and MMSE, CDR, 
ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) at the Baseline 
Visit.
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
Page 1298 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 75 of 146
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild to moderate AD.  (revised per Amendment 01)  
It also shows sensitivity to treatment effects with AChEIs.  The ADCOMS assesses both 
cognitive and functional domains and can be offered as a single primary clinical endpoint.  
The ADCOMS has a range from 0 to 1.97.  
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test where the subject presses a key when the card 
is turned face up from a pack of cards (“Has the card turned over”).  Speed of 
response is the measure.
2. Identification – a simple choice reaction time test where the subject presses 1 of 2
keys when the card just turned face up is either a red card or a black card (“Is the card 
red”).  Speed of response is the measure.
3. One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial 
or not (“Is the previous card the same”).  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not 
in the task (“Have you seen this card before in this task”).  Accuracy of response is 
the measure.
ISLT: The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects are read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Mini Mental State Examination: A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:
The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire:
Either a caregiver or informant or the subject 
provides performance ratings (from 0 to 3) on 10 complex activities of daily living performed 
within the preceding 4 weeks.  Scores range from 0 (independent) to 30 (dependent).  
9.5.1.3.2
VOLUMETRIC MRI
Page 1299 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 76 of 146
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
CSF samples will be collected by LP (gravity drip method) at the timepoints specified in 
Table 6 and Table 7.  The CSF sample taken at the Baseline Visit will only be performed 
after confirmation of an amyloid positive PET scan. See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed, depending on emerging 
data from other studies with E2609.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
Page 1300 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 77 of 146
at the ED Visit) the PK blood sample should be collected shortly before or shortly after 
completing the LP. (revised per Amendment 01)  Although the PK sampling procedures at 
the ED visit should follow those of Visit 18, in the event that study drug has already been 
discontinued prior to the ED visit, then no dosing will be conducted. However, a PK sample 
at trough (before LP) will be collected, followed by LP at approximately the same time as 
previous visits.  A second PK blood sample will be collected as close as possible in time to 
the LP, either shortly before or shortly after the LP.  (revised per Amendment 01)
Blood will also be drawn where possible at the first report of an SAE or severe unexpected 
AE and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  At Baseline, a CSF sample will be collected by LP (gravity drip method) after 
fasting (preferred), or at least 2 hours after the most recent meal.  The timing of the Baseline 
LP needs to be scheduled carefully such that subsequent LPs (Visit 7 and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each 
individual subject.  At visits where cognitive tests are also performed, if the tests are to be 
performed on the same day, the LP must be performed after the cognitive tests have been 
completed and the subjects should rest and drink some fluid to hydrate before the LP.  
(revised per Amendment 01) The CSF sample will not be taken at the ED Visit if this visit 
occurs within 3 months of a previous CSF sample.  The CSF sample will be used for PD 
assessments including but not limited to CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE.  
The plasma sample will be used for Aβ(1-x) analysis and may be used for exploratory 
biomarker analyses (eg, miRNA).  Aβ(1-x) in both CSF and plasma will be measured using a 
commercially based enzyme-linked immunosorbent assay (ELISA).  The pre- and post-
screening analysis of CSF Aβ(1-42), t-tau, and p tau will be performed using ELISAs.  
BACE1 levels will be measured using internally developed fluorescence resonance energy 
transfer and ELISA based assay(s).  Substrates of BACE1 inhibition may also be explored 
using Western blots or other amenable methodology if clinical observations warrant and if 
analytes can be reliably tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected on the same day 
shortly before or shortly after completing the LP at Baseline.  The sample should be collected 
at fasting or at least 2 hours after the most recent meal.  (revised per Amendment 01)
At the Baseline Visit, CSF and blood samples will be collected and stored for determination 
of prior exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
Testing may include, but not be limited to, serological tests, viral titer by quantitative 
polymerase chain reaction, or human leukocyte antigen genotyping.
Page 1301 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 78 of 146
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any collected CSF 
samples will be stored for up to 15 years.  
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  Longitudinal amyloid PET imaging will also be conducted after 18 months of 
treatment (or at ED, providing the subject has received at least 39 weeks of study drug).  
Longitudinal amyloid PET imaging will only be conducted until acceptable 18-month PET 
scans have been obtained for at least 25 subjects per treatment arm for each amyloid PET 
ligand used (Table 6).  PET scanning will be performed with a locally approved Aβ imaging 
agent, eg, Amyvid. Descriptions and detailed instructions for all imaging can be found in the 
imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
Page 1302 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 79 of 146
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7 will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and posttreatment for exploratory 
immunomodulatory and immune-based analyses.
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments, particularly for the CDR (see Section 9.4.6). (revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not 
necessary to report every sign or symptom as a separate AE if the overall disease 
[diagnosis] is being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, discontinuation of study 
drug, or withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  For subjects 
who discontinue early from study drug but undertake further efficacy assessments, AEs will 
only be collected for 3 months after the last dose of study drug, ie, through to the second 
follow-up visit (Visit 20).  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
collected for 3 months after the last dose of study drug, ie, through to the second follow-up 
visit (Visit 20).  For subjects who discontinue early from study drug but continue with further 
efficacy assessments, SAEs will be solicited only for 3 months after the last dose of study 
drug, i.e. up to the 2nd follow up visit (Visit 20). However, any SAEs volunteered by 
subjects after this time point must be reported according to standard procedures.
Page 1303 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 80 of 146
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADCOMS, ADAS-cog14, MMSE, and CBB 
(see Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment 
Period, and if this cognitive decline is considered by the investigator to be excessive relative 
to the subject’s recent AD history, this finding should be reported as an AE.
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4.

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following adverse events will require the collection of information sufficient to provide a 
detailed description of the event, treatment and outcome to the Medical Monitor for the 
study: any treatment-emergent significant laboratory abnormality; any seizures, herpes zoster 
infection, severe infection; any moderate to severe drug rash or any rash lasting more than 
Page 1304 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 81 of 146
72 hours (regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
All AEs must be followed through the second follow-up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study 
treatment

The course of the event, especially the effect of discontinuation of study treatment 
or reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with 
other similar treatments

The presence of risk factors in the study subject known to increase the occurrence 
of the event

The presence of nonstudy, treatment-related factors that are known to be 
associated with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Page 1305 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 82 of 146
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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)
Page 1306 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 83 of 146

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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection. Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils), and 
(Screening and Beseline only), PT, PTT, and INR
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte subset analyses (see Table 5).  Regulatory T cells will be measured using 
CD4, CD25, and CD127 cell surface markers and FoxP3 intracellular marker.  
PBMCs
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HBsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononeuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (CD3, CD4, CD8, CD45, CD19, CD16, CD56, and CD14) 
and total lymphocyte counts will be measured in order to provide the lymphocyte subset data 
as shown in Table 5.  In addition, Regulatory T cells will be measured using CD4, CD25, and 
CD127 cell surface markers and FoxP3 intracellular marker.  
Page 1307 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 84 of 146
Table 5
Lymphocyte Subtyping 
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
in the supine position for at least 5 minutes.
Page 1308 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 85 of 146
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the
detection of vasogenic edema and T2* Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.
MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging 
should be conducted within the 7 days before Visits 14, 16, and 18 and at the second 
Follow-Up Visit (Visit 20).  In the event of an Unscheduled Visit, the investigator in 
consultation with the sponsor will determine whether or not a safety MRI should be 
conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed 
during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and Follow-Up Visits at 4 weeks and 12 weeks 
after the last dose of treatment.  Subjects will also undertake an Unscheduled Visit (with 
MRI) at approximately 30 days after the visit at which such MRI features were first 
Page 1309 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 86 of 146
identified.  Additional visits may be arranged if clinically indicated in the opinion of the 
investigator, and may occur later than 12 weeks after the final dose of study drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance,
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve.  Treatment-emergent abnormal neurological 
findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Period, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 1310 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 87 of 146
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF, blood, and DNA samples will be collected and may be 
used for exploratory biomarker analyses, as well as tested in the event that a subject develops 
AEs that warrant further investigation.  
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 1311 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 88 of 146
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/ Assessments (to be completed in a maximum of 50 days)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Demographics
X (Tier 1)
Medical historya
X (Tier 1)
Prior / concomitant medicationsb
X (Tier 1)
X
Vital signs including weightc 
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTd
X (Tier 1)
X
MMSEd
X (Tier 1)
X
CDRd
X (Tier 1)
X
FAQd
X (Tier 1)
X
ADAS-cog14d
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGe
X (Tier 2)
X
Blood and urine for clinical laboratory testsf
X (Tier 2)
X
Blood for lymphocyte subset analysesg
X (Tier 2)
X
Blood for Ig analysesh
X (Tier 2)
X
Blood for viral screeni
X (Tier 2)
Blood for thyroid function testsj
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIk
X (Tier 3)
Amyloid PET scanl
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagem
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinations
X
Ophthalmic assessmentt
X
Page 1312 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 89 of 146
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
AchEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = Inernational Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time,TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence. Tier 2 procedures may be performed on the same day as Tier 1 procedures, as long as the results of 
all Tier 1 procedures (eg, delayed recall on the ISLT) show that the subject is eligible to continue with screening activities.
Similarly, all screening assessments and procedures must be completed, and eligibility to continue in the study confirmed, 
before any baseline assessments and procedures commence.  Adverse events and eligibility against inclusion and 
exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  (revised per 
Amendment 01)  
Note:  All screening and baseline assessments are to be completed within 50 days.  The interval between availability of the 
results of the last screening assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as 
possible and ideally should not exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur 7 to 10 days after 
completion of the Baseline visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is 
required to take Exclusion Criterion #19 into account.  Thus, the total Prerandomization Phase may be up to 60 days.
a:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  
b:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
c:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
d:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  
The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, ISLT (delayed recall), and CBB 
(repeat CBB for additional practice) at Screening; and MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), 
CBB, and ISLT (delayed recall) at the Baseline Visit.  At visits where the CDR or FAQ are conducted, the 
investigator will determine whether the caregiver or informant must attend in person or whether telephone contact 
will be suitable, and will base this determination upon the functional ability of the subject among other factors.
e:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
f:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
g:
Lymphocyte subsets to be measured include CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), 
CD16/CD56 (natural killer cells) and CD14 (macrophages).  Regulatory T cells will also be measured (CD4, CD25,
and CD127, FoxP3).  Viability staining may also be employed.
h:
Igs to be analyzed include IgG, IgA and IgM.
i:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
j:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine and free thyroxine.
k:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images.
MRI will be read by an approved central reader.  
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI 
assessments in the same imaging session. (revised per Amendment 01)
l:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.
m:
CSF will be collected by LP after fasting (preferred), or at least 2 hours after the most recent meal.  A gravity drip 
collection method must be used.  Subjects will be encouraged to stay at the site after completion of LP for medical 
Page 1313 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 90 of 146
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
observation.  The timing of the Baseline LP needs to be scheduled carefully such that subsequent LPs (Visit 7 and 
Visit 18) can be performed at a similar time of day (±1 hour) for each individual subject. If the LP and cognitive tests 
are performed on the same day, the LP must be performed after the cognitive tests have been completed and the 
subject should rest and drink some fluid to hydrate before the LP.  The CSF sample will be used for PK and PD 
assessments.  A CSF sample will also be stored for testing in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection). (revised per Amendment 01)
n:
The PK blood sample should be collected on the same day shortly before or shortly after completing the LP.  The 
sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
o:
The PD and exploratory biomarker blood sample should be collected shortly before or shortly after completing the LP.  
The sample should be collected at fasting or at least 2 hours after the most recent meal. (revised per Amendment 01)
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops treatment-emergent adverse events that 
warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether 
the subject already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurological examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 1314 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 91 of 146
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological assessment via 
photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Blood samples for lymphocyte subset
analysesl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Blood samples for Igsm
X
X
X
X
X
X
X
X
Xe
X
Blood samples for isolation of PBMCs 
X
X
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample for storage for immune statuso
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 1315 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 92 of 146
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xe
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and exploratory 
biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 1316 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 93 of 146
Notes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled.
a:
Visit 3 should be conducted 7 to 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless additional 
time is required to take Exclusion Criterion #19 into account.  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A window of ±10 days will be permitted for 
Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit windows, every effort should be made to bring 
the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20, respectively).  Subjects who discontinue study drug prematurely will also be 
scheduled to return to the study site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these visits have 
not already been performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB, and ISLT) will be conducted.   Regularly scheduled 
clinical efficacy visits do not need to be attended if they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days of either of the Follow-Up 
Visits (Visit 19 and Visit 20).  Subjects who discontinue early from study drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 2 posttreatment Follow-Up visits; 
one 4 weeks after the last dose of study drug and a second 12 weeks after the last dose of study drug (Visit 19 and Visit 20 respectively).  If clinically indicated, more frequent 
safety assessments can be made as UNS assessments or visits during the posttreatment Follow-Up period.  
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  However, lymphocyte subsets and Igs should 
be repeated at Visit 20 if they were outside of the normal range (regardless of clinical significance) at Visit 19.
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern, eg, 
depigmentation, rash, herpetic lesion.
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets to be measured include CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and total 
lymphocytes.  Regulatory T cells will also be measured (CD4, CD25 and CD127, FoxP3). Viability staining may also be employed.
Page 1317 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 94 of 146
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors. 
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images 
inMRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging should be conducted within the 
7 days before Visits 14, 16, and 18 and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the sponsor will determine whether or not a safety MRI 
should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  A volumetric MRI sequence will be 
collected in all subjects immediately following all safety MRI assessments. (revised per Amendment 01)
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14 and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly before or shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK 
sample will still be collected, followed by LP at approximately the same time as at previous visits. A second PK blood sample will be collected as close as possible to the LP, 
either shortly before or shortly after the LP. (revised per Amendment 01)
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
All visits at which CSF samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. A CSF 
sample will be collected by LP between 4 and 8 hours postdose and at the same time of day as the subject's Baseline LP (±1 hour).  The CSF sample will be taken with the 
subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  If the LP and the cognitive tests are performed on the 
same day, the LP must be performed after the cognitive tests have been completed and the subject should rest and drink some fluid to hydrate before the LP.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a 
previous CSF sample. If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the CSF sample will still be collected unless it was 
already collected within the past 3 months. (revised per Amendment 01)
w:
Subjects reporting adverse events relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time for post-dose 
medical observation.
Page 1318 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 95 of 146
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.1.1.1, and Figure 2.
See Section 9.5.1 for a full description of the procedures and assessments to be performed 
during this study.
Table 8
presents the number of blood and CSF samples, and the total volume of blood 
and CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline 
Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
18
2 x 5 mL
16 x 5 mL
90 mL
Lymphocyte subset analyses
18
2 x 4 mL
16 x 4 mL
72 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
9
2 x 2 mL
7 x 2 mL
18 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
322  mL
402  mL
CSF
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 1319 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 96 of 146
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the second follow-up visit (Visit 20).  In subjects who 
discontinue study drug early, but continue with efficacy assessments, SAEs only need to be 
solicited up to 3 months after the last dose of study drug.  However, any SAEs volunteered 
by subjects after this time point must be reported according to standard procedures.  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.
Page 1320 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 97 of 146
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Page 1321 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 98 of 146
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
Page 1322 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 99 of 146
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 4 and 12 weeks after the last dose of study drug 
(Visit 19 and Visit 20, respectively) (see Section 9.1.2.3).  See Table 7 for full details of the 
assessments to be performed at these visits.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when 
clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18, if 
these visits have not already been performed).  At these visits, only clinical efficacy 
assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  
Subjects who discontinue early from study drug are considered on study as long as they 
return for their regularly scheduled clinical efficacy visits as outlined above. Subjects who 
discontinue study drug early (as opposed to subjects whose dosing with study drug is 
temporarily suspended under Medical Monitor guidance) will not be permitted to restart 
study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
Page 1323 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 100 of 146
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
Page 1324 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 101 of 146
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

The derived ADCOMS at 18 months of treatment in mild to moderate AD subjects
(revised per Amendment 01)  
Page 1325 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 102 of 146
9.7.1.1.3
EXPLORATORY ENDPOINTS
(revised per Amendment 01)  
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild to 
moderate AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild to moderate AD 
subjects as measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild to 
moderate AD subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild to moderate AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild moderate AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal and 
mild moderate AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 and, 
18 months in MCI/Prodromal and mild to moderate AD subjects as measured by 
vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal 
and mild to moderate AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild to moderate AD 
subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol.  The PP Analysis Set will be used to conduct a 
sensitivity analysis of the primary efficacy endpoint.  Details of the evaluability 
criteria will be determined before database lock and treatment unblinding, and will be 
specified in the statistical analysis plan.
Page 1326 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 103 of 146

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement 
and at least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical population (MCI/Prodromal 
AD or mild to moderate AD).  (revised per Amendment 01)  
Page 1327 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 104 of 146
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
WHO DD preferred term.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be defined as medications 
that (1) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (2) started on or after the date of the first dose of study drug up to the
date of the last dose.  All medications will be presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy Analyses
The MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  
Page 1328 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 105 of 146

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
All mild to moderate AD subjects will be included in the efficacy evaluations of the Mild to 
Moderate AD cohort.  The analysis of the Mild to Moderate AD cohort is based on the group 
sequential design.  Interim analyses in the Mild to Moderate AD cohort will only be 
performed after the MCI/Prodromal cohort crosses the early success boundary.  The early 
efficacy signal based on the change from baseline of ADCOMS at 18 months is defined as 
crossing the interim-analysis boundaries for overwhelming efficacy in the mild to moderate 
AD population.  The O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha 
spending function will be used to assess overwhelming efficacy.  The corresponding OF 
boundaries based on P values will be 0.076, 0.0221, and 0.0423 for the first, second, and 
final analyses, respectively, according to 2 planned interim analyses at the 60% and 80% 
information fraction. (revised per Amendment 01)  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Sensitivity analysis of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  
Page 1329 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 106 of 146

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the PP set and as such, no multiplicity adjustments will be 
made to account for the interim analyses.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild to moderate AD.  If there is no treatment group-by-population interaction 
in the overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild to 
moderate AD) in the overall study.  Otherwise, the MMRM analysis will only include 
subjects in the Mild to Moderate AD cohort.  The comparison between placebo and active 
doses will be performed within mild to moderate AD subjects regardless of subjects included 
in the MMRM analysis.  Dunnett’s method will be used to control for multiplicity due to 
multiple comparisons. (revised per Amendment 01)  
Page 1330 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 107 of 146
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
(revised per Amendment 01)  
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild to moderate AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild to 
moderate AD subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 
months in mild to moderate AD subjects.  Data from early discontinuations will also 
be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild to moderate AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild to 
moderate AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 
months in MCI/Prodromal and mild to moderate AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild to moderate AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild to moderate AD 
subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 
and 18 months in MCI/Prodromal and mild to moderate AD subjects
Page 1331 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 108 of 146
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual E2609 concentration listings.  The PK 
Analysis Set will be used for summaries of E2609 concentrations. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in CSF will 
be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  The PK/PD relationship between plasma PK parameters with other 
biomarkers may also be explored using similar methods.
Additionally, the relationship between plasma and CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between plasma and CSF exposure to E2609 
and the change from baseline for 18 months in the ADAS-cog, the CDR, and the MMSE,
will be explored graphically.  Any emergent relationship will be explored through population 
PK/PD modeling.
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
Page 1332 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 109 of 146
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the 
AE is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum severity (mild, moderate, or severe).  The number (percentage) of subjects with 
Page 1333 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 110 of 146
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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with treatment-
related TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical population 
(MCI/Prodromal or mild to moderate AD). (revised per Amendment 01)  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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 
Page 1334 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 111 of 146
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a Grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a Grade of 3 or higher.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
Page 1335 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 112 of 146
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE, CDR, and CBB (see 
Section 9.7.1.6).
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Page 1336 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 113 of 146
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 0.15 
(SUVR), respectively; this would require a total of 100 subjects from all 4 arms at 18 months 
to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild to Moderate AD Cohort (revised per 
Amendment 01)  
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the Mild to Moderate AD cohort in Section 9.7.1.6.2.  
The statistical power was estimated through simulation for the dose-response assumption that 
the percent reduction in change from baseline of ADCOMS at 18 months compared with 
placebo would be 33% and 50% corresponding to the 2 doses, respectively.  The estimated 
power for the actual planned 200 mild to moderate AD subjects is approximately 80% 
assuming a 2-sided alpha of 0.05.  (revised per Amendment 01)
9.7.3
Interim Analysis
An interim safety analysis will be conducted when the first 60 subjects have completed 
12 weeks of treatment (or discontinue study drug early) in Stage A. (revised per 
Amendment 01)  
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
Page 1337 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 114 of 146
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, including MCI/Prodromal subjects from 
Stage A and Stage B).  (revised per Amendment 01)  Further interim efficacy analyses will 
be conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
The Mild to Moderate AD Cohort (revised per Amendment 01)  
A group sequential design will be used for the Mild to Moderate AD cohort.  (revised per 
Amendment 01)  This design includes 3 looks, 2 interim looks (when 60% and 80% 
information fractions are achieved) and 1 final look.  The information fraction is the number 
of assessments in all treatment arms divided by the total number of expected assessments.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the 
first, second, and final analyses, respectively.  If the actual information fraction during the 
interim analyses is different from 60% or 80% at the interim, the efficacy boundaries will be 
adjusted based on the actual information fraction.  
Page 1338 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 115 of 146
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild to moderate AD subjects.  In the event of futility in the 
MCI/Prodromal cohort, an analysis will be performed for the Mild to Moderate AD cohort 
based on the data for mild to moderate AD subjects available at that time. (revised per 
Amendment 01)  
Randomization into the Mild to Moderate AD cohort will remain at a fixed schedule 
throughout Stage B.  (revised per Amendment 01)  
The interim analyses in the Mild to Moderate AD cohort will be conducted by an
independent analysis group.  (revised per Amendment 01)  
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 MCI/Prodromal subjects randomized in the study (1:1:1:1; placebo to each of the 3 
active doses for the first 100 MCI/Prodromal subjects randomized, including those 
randomized from both Stage A and Stage B).  Thereafter, randomization probabilities to each 
treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  (revised 
per Amendment 01)  
Randomization in the Mild to Moderate AD Cohort (revised per Amendment 01)  
In Stage A, the mild to moderate AD subjects will be randomized to placebo or 1 of 3 E2609 
dose groups (5 mg, 15 mg, and 50 mg of E2609) at a 1:1:1:1 ratio, while in Stage B, the mild 
to moderate AD subjects will be randomized to placebo or 1 of 2 E2609 dose groups (15 mg 
and 50 mg E2609) at a 1:1:1 ratio. (revised per Amendment 01)  
Stratification (revised per Amendment 01)  
Within the 2 clinical cohorts (MCI/Prodromal and mild to moderate AD), subjects will be 
stratified at randomization by ApoE4 status (positive or negative) and prior treatment with 
AChEIs or memantine or both (yes or no). (revised per Amendment 01)  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 1339 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 116 of 146
10 REFERENCE LIST
(revised per Amendment 01)
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology 
2007;68:1588-95.
Page 1340 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 117 of 146
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry. 2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on 
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hu W, Watts K, Shaw L, Howell J, Trojanowski J, Basra S, et al.  CSF beta-amyloid 1–42 –
what are we measuring in Alzheimer's disease?.  Ann Clin Transl Neurol. 2015;2(2):131–39.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Page 1341 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 118 of 146
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Page 1342 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 119 of 146
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
25.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 1343 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 120 of 146
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 1344 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 121 of 146
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for 
accuracy after production

Recorded data from automated instruments such as IxRS, x-rays, and other 
imaging reports (eg, sonograms, computed tomography scans, MRIs, radioactive 
images, ECGs, rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 1345 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 122 of 146
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 1346 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 123 of 146
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 CTA 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 CTA 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 CTA executed between the 
institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
Page 1347 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 124 of 146
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 01)
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
not applicable
<700 – 500/mm3
<0.7 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
not applicable
<1.4 – 1.0109/L
<1400 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
<3.6 g/dL – 3 g/dL
69 -79 years (LLN-ULN)
<3.5g/dL – 3g/dL
79 -89 years (LLN-ULN)
<3.5g/dL – 3g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Male:
>44 – 3.0 x 44
Female:
>3.0 – 5.032
Male
>3.0 – 5.044
Female:
>5.0 – 20.032
Male:
>5.0 – 20.044
Female:
>20.032
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Page 1348 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 125 of 146
Grade 1
Grade 2
Grade 3
Grade 4
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>3.0 mg/dL – 6.0 1.27
Female
>6.01.00
Male
>6.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
not applicable
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
not applicable
>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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 1349 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 126 of 146
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and 
Listing 6.  Medications permitted with restrictions are listed in Listing 7, Listing 8, and 
Listing 9.  These may not be all-inclusive listings.  Please contact the medical monitor(s) if 
the investigators have any questions or concerns regarding any medication not listed that 
your subjects may be taking before enrollment or start during the course of the E2609-G000-
202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 9 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 1350 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 127 of 146
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Blaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Page 1351 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 128 of 146
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 1352 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 129 of 146
Listing 2 Prohibited Medications Within 7 Days (or 5 Half-lives, Whichever is Longer) 
Before Randomization and Until after the Last Treatment Visit)
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names 
may be the ® or ™)
Anticoagulants
Adeporin
Normiflo
Alteplase, tPA
Activase, Cathflo Activase
Anisindione
Miradon
Antithrombin III
ATryn, Thrombate III
Argatroban
Argatroban
Bivalirudin
Angiomax
Dabigatran
Pradaxa
Dalteparin
Fragmin
Danaparoid
Orgaran
Dicumarol
Dicumarol
Enoxaparin
Lovenox
Fondaparinux 
Arixtra
Heparin Sodium
Monoject
Lanoteplase
Lanoplase
Lepirudin
Refludan
Pentosan polysulfate 
sodium
Elmiron
Reteplase
Retavase, Retevase
Staphylokinase
Eskinase, Heberkinasa Kabikinase, Streptase, Thrombosolv, Zykinase
Streptokinase
Streptase
Tenecteplase
TNKase
Tinzaparin
Innohep
Urokinase
Abbokinase, Kinlytic
Warfarin
Coumadin, Jantoven
Antiplatelet drugs
Aspirin and Plavix 
(revised per 
Amendment 01)
Aspirin or clopidogrel is permitted in all subjects.  Aspirin and clopidogrel in 
combination is not permitted (revised per Amendment 01)
Note:  This list is not exhaustive.
Page 1353 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 130 of 146
Listing 3 Prohibited Medications Within 5 Half Lives or 60 Days, Whichever is 
Longer, Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
Page 1354 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 131 of 146
Listing 4 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 1355 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 132 of 146
Listing 5 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 1356 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 133 of 146
Listing 6 Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 1357 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 134 of 146
Permitted Prior/Concomitant Medications
Listing 7
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Follow-Up Visit 2
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 1358 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 135 of 146
Listing 8
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph 
SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
PRN = Pro re nata
Page 1359 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 136 of 146
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 8.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 1360 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 137 of 146
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone
Risperdal
Thioridazine
Mellaril
Thiothixene
Navane
Trifluoperazine
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Page 1361 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 138 of 146
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 1362 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 139 of 146
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
Page 1363 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 140 of 146
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
Page 1364 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 141 of 146
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 1365 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 142 of 146
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Relaxed
Increased well-being
Page 1366 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 143 of 146
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Page 1367 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 144 of 146
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 1368 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 145 of 146
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product 
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 1369 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:  v3.0, 28 May 2015
Confidential
Page 146 of 146
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof-of-Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate 
Dementia 
Due 
to 
Alzheimer’s 
Disease
(revised 
per 
Amendment 01)
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 1370 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page i of v
REVISION HISTORY
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, 
etc.
Compliance with current company 
style guide and for general 
consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Synopsis - Inclusion/Exclusion 
Criteria

Section 9.1.2.3

Section 9.3.1

Section 9.3.2

Section 9.5.1 (related 
subsections)

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Clarified classification of MCI due 
to AD
Clarification that MCI due to AD 
population will also be consistent 
with the research criteria for 
Prodromal AD in that impaired 
episodic memory is required and 
will be tested using a list learning 
task (the International Shopping 
List Task)

Synopsis – Study Design

Section 9.1
Replaced “enroll” with 
“randomize,” pertaining to subject 
entry into study
Correction to terminology

Synopsis – Study Design

Section 9.1

Section 9.3
Added criterion excluding subjects 
with hepatic impairment and total 
bilirubin greater than 1.5×ULN or 
INR greater than 1.7 at Screening 
or Baseline.  Subjects with 
Gilbert’s syndrome need not be 
excluded.
At request of FDA, exclude 
subjects who have hepatic 
impairment

Synopsis –
Inclusion/Exclusion  Criteria

Abbreviation List

Section 9.3.2
Added coagulation parameters for 
prothrombin time (PT), partial 
thromboplastin time (PTT), and 
International Normalized Ratio
(INR) to screening and baseline 
procedures
Screen for hepatic impairmnent

Synopsis –
Inclusion/Exclusion Criteria

Abbreviation list

Section 9.3.2

Table 4

Table 6

Table 8
Page 1371 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page ii of v
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
For subjects who discontinue study 
drug prematurely, conduct efficacy 
assessments postdose at same time 
points as subjects who continue in 
the study.  Added FAQ to this set 
of efficacy assessments.
To facilitate efficacy analyses, 
which are based on longitudinal 
modeling for all subjects

Synopsis –Study Design 

Section 9.1.2.2

Section 9.3.3

Section 9.5.4.1

Section 9.5.5

Table 7
Delete diagram of E2609 structure
This display is not needed for the 
protocol. The Investigator’s 
Brochure has this information.

Section 9.4.2.1
Additional blood samples to be 
taken at Visits 19 and 20
Samples are to be put in storage to 
allow for assessment of immune 
status at end of study, as needed.

Synopsis - Assessments

Table 8
Add subheadings to Section 9.7 
describing the primary endpoint 
analysis, and text clarifying that no 
multiplicity adjustments will be 
done to account for the interim 
analyses
To distinguish clearly the primary 
analysis and the sensitivity 
analyses of the primary endpoint  

Synopsis - Efficacy Analyses

Section 9.7.1.6.1
Clarification of PK sampling upon 
Early Discontinuation
Additional operational details of 
the timing of the PK sampling at 
the ED visit provided

Section 9.5.1.4.1

Table 7
Clarification of ApoE testing
Clarification that the ApoE genetic 
testing will be for homozygous or 
heterozygous E4, versus non-E4

Section 9.5.1.4.2
Revision to PK/PD interim 
analysis text
Confirm that interim PK/PD 
analysis will be conducted by an 
independent group

Section 9.4.6
Addtion of text regarding safety 
signals with E2609
To provide information on safety-
driven dose adjustments

Synopsis – Study Design

Section 9.1
Addition of PBMC 
collection/assessment at Baseline,
during treatment, and posttreatment  
Recent animal studies have shown 
an effect of E2609 on this model so 
they will be added to the 202 
clinical study as an additional 
exploratory assessment.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Table 4

Table 6

Table 7

Table 8
Stipulate that exploratory 
biomarker analyses may be 
conducted using blood or CSF
samples that may have been drawn 
for other purposes
To allow more flexibility for 
possible exploratory biomarker 
studies associated with study drug 
or disease, including miRNA and 
DNA

Synopsis - Assessments,

Abbreviation list 

Section 9.5.1.4.2

Section 9.5.1.5.12

Table 6

Table 7
Page 1372 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page iii of v
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Prohibit concomitant medications 
that are strong CYP3A4, inhibitors, 
but clarify that no restrictions are 
needed for other CYP3A4 
inhibitors, CYP3A4 inducers, or 
CES2 inhibitors
At request of FDA, in light of 
finding that inhibition of CYP3A4 
by a reference agent increases 
plasma levels of E2609

Synopsis - Concomitant 
Drug/Therapy

Section 7.1

Section 9.4.7

Appendix 2(Listing 6)
Addition of tests for viral 
characterization at Baseline
To confirm by serology 
information of subjects prior 
exposure to common viruses pre-
dosing with study drug

Section 9.5.1.2.2

Table 4

Table 6

Table 8
Use of a centralized dermatologist 
assessment via photography
A centralized approach, using 
standardized photography, to FDA-
required serial dermatological 
assessments will be employed for 
consistency of assessments 
between sites and for consistency 
of longitudinal assessments of 
individual subjects.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5

Section 9.5.1.5.8

Table 6

Table 7
Removal of testing for 
benzodiazepines or opioids as part 
exclusion criteria #35
To differentiate appropriate 
medicinal use from recreational 
drug use or abuse

Synopsis – Exclusion Criteria

Section 9.3.2
Addition of analysis of other 
covariates such as adjusted 
hippocampal volume will be 
studied
Hippocampal volume has been 
shown to correlate with rate of 
cognitive decline and as such is a 
key covariate to be used in the 
analyses.

Synopsis – Analysis of 
Primary Endpoint

Section 9.7.1.6.1
Addition of clarifications to 
ophthalmic examination
To provide more detail around the 
requirements for the ophthalmic 
exam

Synopsis – Safety Assessments

Section 9.5.1.5.13

Table 6

Table 7
Addition of details regarding 
specific method of CSF collection 
(ie, gravity drip)
Use of materials required for 
suction method when collecting 
CSF can affect the PD data and so 
it is important to make it clear that 
only the gravity drip method can be 
used for collecting CSF in this 
study for protecting the quality and 
the consistency of the CSF PD 
data.

Section 9.5.1.3.3

Section 9.5.1.4.2

Table 6

Table 7
Addition of specific testing for B12 
levels at Screening
Abnormally low serum vitamin 
B12 levels are exclusionary for the 
study (excl criterion 8) but a blood 
draw for Vit B12 was inadvertently 
missed out of Table 6 in protocol 
version 1.

Synopsis – Exclusion Criteria

Section 9.3.2

Section 9.5.1.2.3

Figure 2

Table 6
Page 1373 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page iv of v
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Addition of details regard AEs that 
might be signals of possible drug 
abuse potential
Changed terminology re: collection 
of additional information for AEs 
that might be signals of possible
abuse potential.  No longer use the 
word "narrative" in order to avoid 
potential confusion with standard 
clinical trial narratives eg, for 
serious adverse events,   adverse 
events leading to withdrawal, etc.

Synopsis – Safety Assessments

Section 9.2.6

Section 9.5.1.5.1

Appendix 4
Addition of clarification regarding 
position for taking vital signs (ie, 
supine)
The American Heart Association 
guidelines only mention supine, 
standing, and sitting as positions 
for taking HR and BP 
measurements.  Therefore, have 
changed required position from 
semi-supine to sitting.

Section 9.5.1.5.4

Table 6

Table 7
Stipulated that study drugs are to 
be taken with food
For consistency of treatment 
conditions

Section 9.5.1.4.1
Change to list of Study Specific 
AEs which should be considered 
SAEs
Eisai's standard procedures have 
changed such that non-serious 
study specific adverse events of 
interest are no longer reported to 
Eisai Product Safety; instead, any 
additional information required for 
such non-serious adverse events 
will be obtained through other 
methods.  In addition, certain 
events (new onset seizures, ocular 
herpes) are now to be classified as 
serious as important medical 
events, regardless of whether they 
meet standard ICH serious criteria.

Section 9.5.1.5.1

Section 9.5.1.5.2
Increased  blood volume for PK
To match collection tubes and 
ensure sufficient sample for 
planned assays

Table 8
Corrected error in definition of PK 
analysis set
For accuracy

Synopsis – Study Endpoints

Section 9.7.1.2
Page 1374 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page v of v
Revisions to Version 1.0
New version/date: Version 2.0, 21 Oct 2014
Change
Rationale
Affected Protocol Sections
Addition of details regarding 
discontinuation of study drug  
To clearly and consistently 
differentiate "discontinuation from 
study drug" from "withdrawal from 
study”

Synopsis

Section 7

Section 9.1.2.1

Section 9.2.6

Section 9.3.3

Table 1

Table 2

Section 9.4.1

Section 9.4.4

Section 9.5.1.5.1

Section 9.5.1.5.3

Section 9.5.5
Re-ordered prohibited medication 
lists
For consistency, all lists re-ordered 
in alphabetical order of generic 
drug name, and footnotes revised 
for overall consistency

Appendix 2
Moved nefazodone from Listing 9 
to Listing 6
Nefazodone is a strong CYP3A4 
inhibitor and is therefore 
prohibited.

Appendix 2
Page 1375 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 1 of 144
1
TITLE PAGE
   
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol 
Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate 
Safety, 
Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive 
Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild Dementia Due to Alzheimer’s Disease
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European Knowledge 
Centre
Mosquito Way
Hatfield, 
Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 Jul 2014 (original protocol)
V2.0
21 Oct 2014 (revised original protocol)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All 
required study documentation will be archived as required by 
regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
Page 1376 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 2 of 144
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-
4-fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, 
Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild Dementia Due to Alzheimer’s Disease
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 25 sites, United States only
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  A maximum of 40 months from initiation of Stage B
Phase 2
Objectives
Primary Objectives
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/ Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol)
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
Mild Dementia due to Alzheimer's Disease (referred to as mild AD throughout the 
protocol)
Secondary Objectives
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI)
Page 1377 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 3 of 144
2. To evaluate the effect of E2609 compared with placebo on amyloid β(1-x) (Aβ[1-x]) in 
cerebrospinal fluid (CSF) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at
18 months in mild AD subjects
Exploratory Objectives
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in 
CSF after 4 weeks and 18 months of treatment in mild AD subjects
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, in 
MCI/Prodromal and mild AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF β-amyloid converting enzyme 1 (BACE1)
measurements during 18 months of treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment and during 
posttreatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
7. To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and 
mild AD subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
Page 1378 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 4 of 144
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild AD subjects
Study Design
This will be a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild AD.  A common set of 
inclusion criteria, consistent with the National Institute on Aging – Alzheimer’s Association 
(NIA-AA) clinical research criteria for Mild Cognitive Impairment (MCI) due to 
Alzheimer’s Disease (AD) or mild AD, will be required for all subjects.  In addition, the 
MCI due to AD population will also be consistent with the research criterion for “Prodromal 
AD” in that episodic memory will be impaired on a list learning task (ISLT).  As the 
non-demented subjects will be consistent with the criteria for both MCI due to AD and 
Prodromal AD they will be identified as MCI/Prodromal subjects in this protocol. The 
diagnosis of MCI/Prodromal AD or mild AD will be based on both clinical and biological 
(ie, confirmation of amyloid load in the brain) criteria.  
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (after the first 
60 randomized subjects have completed 12 weeks of treatment or have discontinued study 
drug early) in MCI/Prodromal subjects before expanding enrollment to include a larger 
population of MCI/Prodromal subjects in Stage B.  In addition, during Stage B of the study, 
subjects with mild AD will be randomized to form a separate mild AD cohort.  All 
MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective of 
whether they were recruited during Stage A or Stage B of the study.  Bayesian adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B.  
Both Stage A and Stage B of the study will consist of 2 phases: Prerandomization and 
Randomization.  The Prerandomization Phase (up to 60 days) includes a Screening Visit
(Visit 1) and a Baseline Visit (Visit 2).  All screening assessments (within 4 distinct tiers)
must be completed, and eligibility to continue in the study confirmed, before any baseline 
assessments commence.  Following successful completion of the Prerandomization Phase, 
eligible subjects will be randomized and will enter the Randomization Phase, which will 
consist of 2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
Stage A
Stage A will randomize 60 eligible MCI/Prodromal AD subjects at Visit 3, 1:1:1:1 to 
4 treatment groups.  In addition to the placebo group, 3 E2609 doses will be used to reduce 
CSF amyloid β levels by approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from 
baseline, respectively, at steady state.  PK/pharmacodynamic (PD) modeling has shown that
these doses should achieve these targets when administered once daily (QD) with food, and 
these doses will be confirmed or adjusted based on the 4-week assessment of CSF Aβ(1-x)
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A of the study, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  The DSMB will make 
Page 1379 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 5 of 144
recommendations to Eisai after each review as to whether any change(s) to the study are 
necessary.  Unless the DSMB recommends otherwise, randomization of subjects into 
Stage A of the study will continue until 60 MCI/Prodromal subjects have been randomized
and dosed.  
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B.  If the 95% confidence interval of the mean percentage change from 
baseline in CSF Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 does not 
include its intended target value (ie, 25%, 50% and 75% reductions from baseline,
respectively for E2609 at 5 mg, 15 mg, and 50 mg QD), PK/PD modeling will be conducted.  
From this model, the new target plasma steady state concentrations of E2609 required to 
achieve the target levels of CSF Aβ(1-x) reduction will be estimated again.  Dose adjustment 
for Stage B may be considered if it is possible to get closer to the new target plasma steady 
state concentrations of E2609 required to achieve the intended target levels of CSF Aβ(1-x) 
reduction than is possible with the initially planned doses, given the limitation that E2609 
dose adjustments will have to be in 5-mg increments or decrements.  Subjects already 
randomized to a dose that needs to be adjusted will be switched to the new adjusted dose and 
complete their treatment at this new dose.
Once 60 MCI/Prodromal subjects in Stage A have completed at least 12 weeks of treatment 
(or discontinued study drug early) an interim safety analysis will be conducted by Eisai and 
the DSMB.  Subjects in Stage A will continue study drug while the DSMB reviews all the 
available safety data, but randomization of additional subjects will not take place (ie, 
recruitment into Stage B will not commence) until the safety analysis is completed by the 
DSMB.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol.  Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are confirmed.  
Stage B will enroll, randomize, and dose up to an additional 440 eligible MCI/Prodromal 
subjects.  In addition, a separate cohort of approximately 200 mild AD subjects will be 
randomized and dosed during Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment to the study is 
completed; following this the DSMB will meet approximately every 6 months.  
Both population cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD) whereas the mild AD cohort 
will only include 2 doses of E2609 (15 mg and 50 mg QD).  
Bayesian adaptive randomization will be used in the MCI/Prodromal cohort only during 
Stage B.  The first 40 MCI/Prodromal subjects recruited into Stage B will be randomized 
according to a fixed schedule (1:1:1:1; placebo: 5 mg E2609: 15 mg E2609: 50 mg E2609) 
Page 1380 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 6 of 144
and the remaining subjects in the MCI/Prodromal cohort in Stage B will be randomized 
according to response adaptive randomizations based on the ADCOMS results using the 
Bayesian interim efficacy analyses.  The mild AD subjects will be randomized according to a
fixed schedule (1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B of the study.
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who 
discontinue study drug prematurely will also be scheduled to return to the study site for each 
scheduled visit when clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 
15, 16, 17, and 18) if these visits have not already been performed.  At these visits, only the 
clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be 
conducted.  Subjects who discontinue early from study drug are considered on study as long 
as they return for their regularly scheduled clinical efficacy visits as outlined above.
Follow-Up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
Number of Subjects

Stage A:  Approximately 250 MCI/Prodromal subjects will be screened to provide 
60 randomized subjects (target of 15 subjects per treatment arm).  

Stage B:  Approximately 1850 MCI/Prodromal subjects will be screened to provide 
up to 440 enrolled subjects.  The final number of MCI/Prodromal subjects will 
depend upon whether the prespecified criteria for either early success or futility are 
met.  In addition, approximately 835 subjects with mild AD will be screened to 
provide approximately 200 randomized mild AD subjects.
Inclusion Criteria
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD 
dementia and is "staged" or classified as either MCI (Stage A and Stage B) or mild 
dementia (Stage B only) and also complies with the following:  
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤20
d.
MMSE ≥20
Page 1381 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 7 of 144
2. Amyloid positive PET image based on centralized PET scan reading 
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitors (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects 
can be entered into the study but there should be no plans to initiate treatment with 
AChEIs or memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization.
Exclusion Criteria
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or magnetic resonance imaging (MRI)
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (eg, arachnoid cysts) or brain tumors (eg, meningioma).
Page 1382 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 8 of 144
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild AD diagnosis or could 
interfere with study assessments or procedures 
7. A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the lower limit of normal 
(LLN) for the testing laboratory) at Screening
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or 
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
12. Any contraindications to lumbar puncture for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
(including subjects known to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization 
20. Any active infection within the last 4 weeks before randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR, etc) must be repeated.
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
Page 1383 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 9 of 144
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
23. Ig (IgG, IgA, or IgM) levels below the LLN
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate electrocardiograms 
(ECGs).  A history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, 
family history of long QT Syndrome) or the use of concomitant medications that prolong 
the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years 
before Screening, current use of recreational drugs or a positive urine drug test at 
Screening.  Subjects who test positive in the urine drug screen need not be excluded if in 
the clinical opinion of the investigator, this is due to the subject taking prior/concomitant 
medications for a medical condition that is not exclusionary and not due to drug abuse.
Page 1384 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 10 of 144
36. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal 
ideation questions 4 or 5, or any suicidal behavior assessment within 6 months before 
Screening, at Screening, or at the Baseline Visit; or has been hospitalized or treated for 
suicidal behavior in the past 5 years before Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications 
section of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can 
be undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, 
or to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period 
and for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 
days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they 
are postmenopausal [amenorrheic for at least 12 consecutive months, in the 
appropriate age group, and without other known or suspected cause] or have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
Page 1385 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 11 of 144
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
or for 28 days after study drug discontinuation.
Study Treatments
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets to 
match E2609 will be of identical appearance.  Each subject will receive 2 tablets, which
when combined will make up the required doses of E2609 (see below) or placebo, to be 
administered orally QD with food.  

MCI/Prodromal Cohort:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or placebo

Mild AD Cohort:  2 doses (15 mg and 50 mg) of E2609 or placebo.  
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 
2 years, comprising: 

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days
(In subjects who have an active infection within 4 weeks of the planned 
randomization date, the duration of the pre-randomization phase can be extended by 
up to 4 weeks to allow additional time for resolution of the infection.)

Treatment Period (Randomization Phase): up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Concomitant Drug/Therapy
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit (see Appendix 2 for a 
detailed listing of these agents):  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-
lives or 7 days (whichever is longer) before randomization

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-
lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization

Live vaccines are not permitted within 3 months before randomization.  This does 
not apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before 
randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Page 1386 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 12 of 144
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which 
are central nervous system (CNS) active and may affect cognitive function, are 
not permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if, in the 
opinion of the investigator, this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of 
selected items (12 total) from 3 fully validated and well established clinical tools, the 
ADAS-cog (4 items), the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should 
be administered in full in the morning, or, if not possible, consistently at the same time of 
day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be 
used since it is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery: A computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test.  Speed of response is the measure.
2. Identification – a simple choice reaction time test.  Speed of response is the measure.
3. One Card Back – a simple working memory test.  Accuracy of response is the measure.
Page 1387 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 13 of 144
4. One Card Learning – a visual learning and memory test.  Accuracy of response is the 
measure.
International Shopping List Task: The ISLT is a verbal learning and episodic memory test 
assessing both immediate and delayed recall.  
Functional Assessment Questionnaire: The FAQ has 10 items concerned with performing 
daily tasks necessary for independent living.  Either a caregiver or informant or the subject 
provides performance ratings on 10 complex activities of daily living performed within the 
preceding 4 weeks.  
Volumetric Magnetic Resonance Imaging: 
vMRI will be used to evaluate disease 
modification, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed depending on emerging 
data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic and Other Biomarker Assessments
Brain atrophy will be measured by vMRI: see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), total tau (t-tau), and p-tau will be measured in 
CSF.  BACE1 levels and activity in CSF will also be measured.  Other exploratory 
biomarkers (eg, miRNA) may also be evaluated in plasma and/or CSF.
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period of the study have amyloid deposition in the brain.  Longitudinal amyloid 
PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging 
will only be conducted through to the time at which acceptable 18-month PET scans have 
been obtained for at least 25 subjects per treatment arm for each amyloid PET ligand used.
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4
homozygous or heterozygous status versus non-carriers and NAT2 status will be used in the 
statistical analysis to determine the effects on treatment response and safety.  Remaining 
genomic DNA may also be stored for up to 15 years to be used to examine the role of DNA 
sequence variability on the absorption, distribution, metabolism, and elimination of E2609, 
development of AEs, as well as the underlying AD.  Variations in E2609 exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
single-nucleotide polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments.  Routine safety assessments will include the monitoring and recording all AEs 
and SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and centralized dermatological 
Page 1388 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 14 of 144
assessments (via photography) at regular intervals.  AEs that might indicate signals of 
possible drug abuse potential will require a more detailed follow-up.  Subjects reporting AEs 
relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency 
and impact of these events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be 
measured (by a centralized laboratory) every week for the first month, every 2 weeks for the 
next 2 months (Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  
Thereafter they will be monitored every 3 months until the end of the Treatment Period and 
at both Follow-Up Visits.  Serum IgG, IgA, and IgM will be monitored monthly for the first 
3 months, at 6, 12, and 18 months, and at both Follow-Up Visits.  
Peripheral blood mononuclear cells (PBMCs) will be collected at Baseline, during treatment, 
and posttreatment for exploratory immunomodulatory and immune-based analyses.
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at baseline and at 3-month intervals during the Treatment Phase of 
the study.  These assessments will specifically include evaluation of any areas of 
depigmentation or rash.  Subjects will also be questioned by the investigator at each visit to 
identify any changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregivers/ informants will be instructed to contact the investigator if they see any 
lesions or other symptoms that might be associated with a drug-induced rash/reaction or 
infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood, DNA, and CSF samples will be taken and stored from all 
subjects.  These samples may be tested for exploratory biomarkers associated with study 
drug or disease, or in the event that a subject develops AEs that warrant further investigation
(eg, to test if a subject with a treatment-emergent infection was exposed to any suspected 
infective agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months
during the Treatment Phase of the study and at the final Follow-Up Visit.  Additional safety 
MRI scans are to be performed as clinically necessary.  MRI acquisition and interpretation 
will be organized centrally to ensure reproducibility and consistency between units involved.  
Full neurological examinations will be performed at Baseline, at 6, 12, and 18 months, and at 
both Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  The neurological examinations will
include muscle strength testing and assessment of cranial nerves including olfaction as well 
as other parts of the CNS.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline 
and at regular intervals throughout the treatment and Follow-Up periods of the study.
An ophthalmic examination (including retinal examination) will be conducted at Baseline. 
An additional examination will be conducted if the subject experiences visual disturbances 
during the course of the study.
Page 1389 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 15 of 144
A number of safety-related criteria for discontinuation of study drug are specified for the 
study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid 
chromatography method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based 
enzyme-linked immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF 
Aβ(1-42), tau, and p-tau will be performed using ELISAs.
BACE1 levels and activity may be measured using a customized assay.  Substrates of 
BACE1 inhibition may also be explored using Western blots or other amenable methodology 
if clinical observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
Secondary Endpoints
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects

The derived ADCOMS at 18 months of treatment in mild AD subjects
Exploratory Endpoints
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild 
AD subjects

Total hippocampal volume at 12 and 18 months of treatment in mild AD subjects 
as measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild AD
subjects
Page 1390 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 16 of 144

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months: ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal 
and mild AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of 
treatment in MCI/Prodromal and mild AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal 
and mild AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 
and, 18 months in MCI/Prodromal and mild AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in 
MCI/Prodromal and mild AD subjects

The population PK parameters of E2609 including the effect of intrinsic and 
extrinsic factors (including NAT2 phenotype) in MCI/Prodromal and mild AD 
subjects
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of 
study drug and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at 
least 1 dose of study drug and have baseline and at least 1 postdose primary 
efficacy measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD 
measurement and at least 1 posttreatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian 
adaptive design.  Frequent interim analyses will be performed to assess the probability of 
early success and futility and to make early stopping decisions.  Response adaptive 
randomization will be used to update the randomization probability among treatment groups 
at each interim analysis.  Key definitions relevant to the Bayesian aspects of the adaptive 
design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.
Page 1391 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 17 of 144

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before
full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild AD cohort: The analysis of the Mild AD cohort is based on the group sequential 
design.  Interim analyses in the Mild AD cohort will only be performed after the 
MCI/Prodromal cohort crosses the early success boundary.  The early efficacy signal based 
on the change from baseline of ADCOMS at 18 months is defined as crossing the 
interim-analysis boundaries for overwhelming efficacy in the mild AD population.  The 
O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha spending function will be 
used to assess overwhelming efficacy.  The corresponding OF boundaries based on P values 
will be 0.076, 0.0221, and 0.0423 for the first, second, and final analyses, respectively, 
according to 2 planned interim analyses at the 60% and 80% information fraction.
Analysis for the primary endpoint 
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, etc), subjects will 
be censored at the time of initiation of treatment with AChEIs or memantine, if they were not 
on these medications at the time of Baseline cognitive assessment (Visit 2), and will be 
censored at the time of dose adjustment of AChEIs or memantine if they were already on 
stable treatment with these medications at the time of   Baseline  cognitive assessment 
Page 1392 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 18 of 144
(Visit 2).  The value of the primary endpoint for censored subjects will be imputed using data 
up to the censoring time and Bayesian longitudinal modeling.
Sensitivity analyses of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis. This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the per protocol set, and as such, no multiplicity adjustments 
will be made to account for the interim analyses.  In case of early success, the conventional 
analyses will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild AD cohort
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild AD. If there is no treatment group-by-population interaction in the 
overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild AD) in 
the overall study.  Otherwise, the MMRM analysis will only include subjects in the mild AD 
cohort.  The comparison between placebo and active doses will be performed within mild 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will 
be used to control for multiplicity due to multiple comparisons.
Analysis for exploratory endpoints
An MMRM will be used to analyze the following exploratory endpoints:  
Page 1393 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 19 of 144

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild AD 
subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 
months in mild AD subjects.  Data from early discontinuations will also be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in 
MCI/Prodromal and mild AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild AD subjects

Change from baseline in left and right hippocampal, whole brain, and total 
ventricular volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal 
and mild AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 
months in MCI/Prodromal and mild AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 
and 18 months in MCI/Prodromal and mild AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.  Summary statistics for CSF biomarkers will be assessed for evidence of a dose 
relationship.
Page 1394 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 20 of 144
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in plasma and 
CSF will be explored graphically and any emergent relationship will be explored through 
population PK/PD modeling.  Additionally, the relationship between CSF exposure to E2609 
and the derived ADCOMS at 18 months, and the relationship between CSF exposure to 
E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  Any emergent relationships will be explored through 
population PK/PD modeling.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  Further information is in the “Pharmacodynamic, 
Pharmacogenomic, 
and 
Other 
Biomarker 
Assessments” 
section. 
 
Details 
of 
pharmacogenomic testing may be provided and reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  Serum IgG, IgM, IgA will be measured and summarized in the same 
manner as other laboratory parameters.
Interim Analyses
The MCI/Prodromal cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be 
conducted by an independent committee that has expertise with Bayesian adaptive design in 
clinical studies.  An unblinded external independent analysis group will provide the interim 
analysis outcomes to the committee at each interim analysis.  The committee will ensure the 
integrity of the interim analysis and response adaptive randomization process through review 
of efficacy data.  In addition, the committee will act in an independent advisory capacity to 
monitor the Bayesian interim analysis outcomes according to the early success and futility 
boundaries prespecified in the protocol.  The committee will not be charged with any subject 
safety issues; this will remain the responsibility of the DSMB.  The DSMB will continue to 
Page 1395 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 21 of 144
monitor the safety aspects of the study throughout Stage A and Stage B.  The study may be 
stopped for safety at any time.
An interim safety analysis will be conducted when the first 60 MCI/Prodromal subjects have 
completed 12 weeks of treatment (or discontinue study drug early).  The first Bayesian 
adaptive interim analysis will be conducted when 100 MCI/Prodromal subjects have been 
randomized into the study (ie, 60 subjects from Stage A and the first 40 subjects from Stage 
B of the study).  Further interim efficacy analyses will be conducted after each additional 50 
MCI/Prodromal subjects have been randomized, up to a maximum of 500 MCI/Prodromal 
subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 500 subjects randomized).  If the 
study reaches full randomization, additional interim analyses will be conducted every 
3 months until all subjects complete 18 months of treatment.  The study will be monitored 
for futility at each interim analysis.  Starting at the 200 subjects’ interim analysis, the study 
will be monitored for success at each interim analysis.  Each interim analysis will be 
conducted on data for the derived ADCOMS.  
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The Mild AD cohort
A group sequential design will be used for the mild AD cohort.  This design includes 3 looks, 
2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the 
first, second, and final analyses, respectively.  If the actual information fraction during the 
interim analyses is different from 60% or 80% at the interim, the efficacy boundaries will be 
adjusted based on the actual information fraction.  If early success in the MCI/Prodromal 
cohort is not achieved before the final analysis that is performed when all subjects have 
completed 18 months treatment, then only a final analysis will be performed in mild AD 
subjects.  In the event of futility in the MCI/Prodromal cohort, an analysis will be performed 
for the mild AD cohort based on the data for mild AD subjects available at that time.  
Page 1396 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 22 of 144
Adaptive randomization in the MCI/Prodromal cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses
[60 patients in Stage A and the first 40 patients in Stage B]).  Randomization probabilities to 
each treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  
Randomization in the Mild AD cohort will remain at a fixed schedule throughout Stage B.
Within the 2 clinical populations (MCI/Prodromal and mild AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or 
memantine or both (yes or no).
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by 
means of simulations.  Extensive study simulations have shown that a total of 500 subjects 
will be sufficient to demonstrate that the most likely ED90 dose achieves a 25% improvement 
over placebo with a probability of at least 80% in the interim and final analyses.  There is at 
least a 90% probability of study success for the dose response scenarios where treatment was 
considered to have a clinically meaningful treatment effect.  Simulations have also shown 
that if there is no obvious dose effect, the probability of falsely claiming superiority to 
placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects 
per group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  
There are 3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false (1-sided).  The null hypotheses will be tested using 
Dunnett’s method with 1-sided alpha of 0.05.  The statistical power was estimated through 
simulation for a moderate dose-response assumption that the percent reduction in change 
from baseline of total hippocampal volume compared with placebo would be 15%, 20%, and 
25% corresponding to the 3 doses, respectively.  The estimated power for actual planned 
study sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  
Under a stronger dose-response assumption (ie, the percent reduction in change from 
baseline of total hippocampal volume compared with placebo is twice as much as that in the 
moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those
for vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, 
a common SD of change from baseline was estimated at 0.33 and a reasonable mean 
difference between treatment and placebo was estimated as 0.25 (standardized uptake value 
ratio [SUVR]).  Assuming a moderate dose-response, the best dose would achieve a 
difference of 0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 
Page 1397 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 23 of 144
and 0.15 (SUVR), respectively, it would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
Sample Size Rationale for the Mild AD Cohort
ADCOMS at Month 18: The null hypothesis is that there is no difference between active 
dose and placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The 
alternative hypothesis is that at least 1 null hypothesis is false.  The null hypotheses will be 
tested using Dunnett’s test with 2-sided alpha of 0.05 as described for the mild AD cohort in 
the secondary analysis section.  The statistical power was estimated through simulation for 
the dose-response assumption that the percent reduction in change from baseline of 
ADCOMS at 18 months compared with placebo would be 33% and 50% corresponding to 
the 2 doses, respectively.  The estimated power for the actual planned 200 mild AD subjects 
is at least 80% assuming a 2-sided alpha of 0.05.
Page 1398 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 24 of 144
3
TABLE OF CONTENTS
REVISION HISTORY......................................................................................................... i
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................29
5
ETHICS............................................................................................................................32
5.1
Institutional Review Boards/Independent Ethics Committees ..............................32
5.2
Ethical Conduct of the Study.................................................................................32
5.3
Subject Information and Informed Consent...........................................................33
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................34
7
INTRODUCTION ...........................................................................................................35
7.1
Nonclinical and Clinical Safety Data.....................................................................36
8
STUDY OBJECTIVES....................................................................................................39
8.1
Primary Objectives.................................................................................................39
8.2
Secondary Objectives.............................................................................................39
8.3
Exploratory Objectives ..........................................................................................39
9
INVESTIGATIONAL PLAN..........................................................................................41
9.1
Overall Study Design and Plan..............................................................................41
9.1.1
Prerandomization Phase...............................................................................44
9.1.1.1
Screening Period..................................................................................44
9.1.1.2
Baseline Period ....................................................................................46
9.1.2
Randomization Phase...................................................................................46
9.1.2.1
Treatment Period..................................................................................46
9.1.2.2
Early Discontinuation ..........................................................................47
9.1.2.3
Follow-up Period .................................................................................47
9.2
Discussion of Study Design, Including Choice of Control Groups.......................47
9.2.1
Overview......................................................................................................47
9.2.2
Rationale for Study Population....................................................................48
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................49
9.2.4
Rationale for Clinical Endpoints..................................................................49
9.2.5
Rationale for Biomarkers.............................................................................51
9.2.5.1
Overall Rationale .................................................................................51
9.2.5.2
Soluble Biomarkers in CSF .................................................................51
9.2.5.3
Amyloid PET .......................................................................................52
9.2.5.4
vMRI....................................................................................................52
9.2.6
Clinical Risks and Mitigation Strategy........................................................53
Page 1399 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 25 of 144
9.3
Selection of Study Population................................................................................54
9.3.1
Inclusion Criteria .........................................................................................55
9.3.2
Exclusion Criteria ........................................................................................56
9.3.3
Removal of Subjects from Therapy or Assessment.....................................59
9.4
Treatments..............................................................................................................62
9.4.1
Treatments Administered.............................................................................62
9.4.2
Identity of Investigational Product...............................................................63
9.4.2.1
Chemical Name and Formula of E2609...............................................63
9.4.2.2
Comparator Drug .................................................................................63
9.4.2.3
Labeling for Study Drug......................................................................63
9.4.2.4
Storage Conditions...............................................................................64
9.4.3
Method of Assigning Subjects to Treatment Groups...................................64
9.4.4
Selection of Doses in the Study...................................................................64
9.4.5
Selection and Timing of Dose for Each Subject..........................................66
9.4.6
Blinding........................................................................................................66
9.4.7
Prior and Concomitant Therapy...................................................................67
9.4.8
Treatment Compliance.................................................................................68
9.4.9
Drug Supplies and Accountability...............................................................68
9.5
Study Assessments.................................................................................................70
9.5.1
Assessments.................................................................................................70
9.5.1.1
Demography.........................................................................................70
9.5.1.2
Baseline Assessments ..........................................................................70
9.5.1.2.1
Medical History and Physical Examinations.................................70
9.5.1.2.2
Viral Testing ..................................................................................71
9.5.1.2.3
B12 Testing....................................................................................71
9.5.1.2.4
TB Exposure Testing .....................................................................71
9.5.1.2.5
Urine Drug Testing ........................................................................71
9.5.1.3
Efficacy Assessments...........................................................................71
9.5.1.3.1
Psychometric Assessments ............................................................71
9.5.1.3.2
Volumetric MRI.............................................................................72
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................73
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................73
9.5.1.4.1
Pharmacokinetic Assessments .......................................................73
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................74
9.5.1.5
Safety Assessments..............................................................................75
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..76
Page 1400 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 26 of 144
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................79
9.5.1.5.3
Laboratory Measurements .............................................................80
9.5.1.5.4
Vital Signs and Weight Measurements..........................................81
9.5.1.5.5
Physical Examinations...................................................................81
9.5.1.5.6
Electrocardiograms ........................................................................81
9.5.1.5.7
Safety MRI.....................................................................................82
9.5.1.5.8
Dermatological Assessment...........................................................83
9.5.1.5.9
Neurological Examination .............................................................83
9.5.1.5.10
Pregnancy Test...............................................................................83
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................84
9.5.1.5.12
Biomarker Samples........................................................................84
9.5.1.5.13
Ophthalmic Examinations..............................................................84
9.5.2
Schedule of Procedures/Assessments ..........................................................84
9.5.2.1
Schedule of Procedures/Assessments ..................................................84
9.5.2.2
Description of Procedures/Assessments Schedule...............................93
9.5.3
Appropriateness of Measurements...............................................................94
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................94
9.5.4.1
Reporting of Serious Adverse Events..................................................94
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................95
9.5.4.3
Reporting of Events Associated with Special Situations.....................95
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................95
9.5.4.3.2
Reporting of Study-Specific Events...............................................96
9.5.4.4
Expedited Reporting ............................................................................96
9.5.4.5
Breaking the Blind...............................................................................96
9.5.4.6
Regulatory Reporting of Adverse Events ............................................97
9.5.5
Completion/Discontinuation of Subjects.....................................................97
9.5.6
Abuse or Diversion of Study Drug ..............................................................98
9.5.7
Confirmation of Medical Care by Another Physician .................................98
9.6
Data Quality Assurance .........................................................................................98
9.6.1
Data Collection ............................................................................................98
9.6.2
Clinical Data Management ..........................................................................99
9.7
Statistical Methods.................................................................................................99
9.7.1
Statistical and Analytical Plans....................................................................99
9.7.1.1
Study Endpoints...................................................................................99
Page 1401 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 27 of 144
9.7.1.1.1
Primary Endpoint...........................................................................99
9.7.1.1.2
Secondary Endpoints .....................................................................99
9.7.1.1.3
Exploratory Endpoints ...................................................................99
9.7.1.2
Definitions of Analysis Sets...............................................................100
9.7.1.3
Subject Disposition............................................................................101
9.7.1.4
Demographic and Other Baseline Characteristics .............................101
9.7.1.5
Prior and Concomitant Therapy.........................................................101
9.7.1.6
Efficacy Analyses ..............................................................................102
9.7.1.6.1
Primary Efficacy Analysis...........................................................103
9.7.1.6.2
Secondary Efficacy Analyses ......................................................104
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................104
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................105
9.7.1.7.1
Pharmacokinetic Analyses...........................................................105
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................105
9.7.1.8
Safety Analyses..................................................................................106
9.7.1.8.1
Extent of Exposure.......................................................................106
9.7.1.8.2
Adverse Events ............................................................................107
9.7.1.8.3
Laboratory Values........................................................................108
9.7.1.8.4
Vital Signs....................................................................................109
9.7.1.8.5
Electrocardiograms ......................................................................109
9.7.1.8.6
Other Safety Analyses..................................................................109
9.7.2
Determination of Sample Size ...................................................................109
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................109
9.7.2.2
Sample Size Rationale for the Mild AD Cohort................................110
9.7.3
Interim Analysis.........................................................................................111
9.7.4
Other Statistical/Analytical Issues .............................................................112
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................113
10
REFERENCE LIST .......................................................................................................114
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....118
11.1
Changes to the Protocol .......................................................................................118
11.2
Adherence to the Protocol....................................................................................118
11.3
Monitoring Procedures.........................................................................................118
11.4
Recording of Data................................................................................................119
11.5
Identification of Source Data...............................................................................119
11.6
Retention of Records............................................................................................120
11.7
Auditing Procedures and Inspection....................................................................120
Page 1402 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 28 of 144
11.8
Handling of Study Drug.......................................................................................120
11.9
Publication of Results ..........................................................................................121
11.10 Disclosure and Confidentiality ............................................................................121
11.11 Discontinuation of Study .....................................................................................121
11.12 Subject Insurance and Indemnity.........................................................................121
12
APPENDICES ...............................................................................................................122
LIST OF IN-TEXT TABLES
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts .................60
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................61
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................65
Table 4
Clinical Laboratory Tests...........................................................................80
Table 5
Lymphocyte Subtyping..............................................................................81
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................85
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................88
Table 8
Summary of Blood and CSF Sample Volumes..........................................93
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study E2609-G000-202.............................................................42
Figure 2
Assessments to be Performed at Screening by Tier...................................45
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................122
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........124
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 137
Appendix 4
AEs Indicating Signals of Possible Drug Abuse Potential ......................140
Page 1403 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 29 of 144
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to x [eg 1-
42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from time zero to 
24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carobxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
Page 1404 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 30 of 144
Abbreviation
Term
ED
early discontinuation
ED90
lowest effective dose that achieves 90% of the greatest treatment effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire (also known as the Functional 
Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ Prodromal 
Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild AD
mild dementia due to Alzheimer’s Disease
miRNA
micro-ribonucleic acid
MMRM
mixed-effects model with repeated measures
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
Page 1405 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 31 of 144
Abbreviation
Term
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
OF
O’Brien-Fleming 
PBMC
peripheral blood mononuclear cell
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
prothrombin time
PTT
partial thromboplastin time
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Study References: On first use, the full study code will be used (eg, E2609-G000-202) with 
a shortened form in brackets (Study 202); thereafter, the shortened form is used.
Page 1406 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 32 of 144
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR)
regarding clinical studies, including Part 50 and Part 56 concerning informed subject 
consent and IRB regulations and applicable sections of US 21 CFR Part 312
Page 1407 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 33 of 144

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for 
studies conducted within any European Union country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
the identified caregiver or informant 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 and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
Page 1408 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 34 of 144
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 125 investigational sites globally (25 sites in the United States for 
Stage A and 125 sites globally for Stage B).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 1409 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 35 of 144
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010, Lu, et 
al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, thus 
accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild AD 
dementia are stages on a single disease spectrum, which follows an Alzheimer’s pathological 
cascade.  Recent consensus papers from the international workgroups of the National 
Institute on Aging-Alzheimer’s Association (NIA-AA), have endorsed this hypothesis 
(Albert, et al., 2011; Jack, et al., 2011; McKhann, et al., 2011; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild dementia due to Alzheimer’s Disease (referred to as mild AD throughout the protocol)
to determine whether the effects of E2609 in this later stage population are comparable with 
those established in the MCI/Prodromal population within this same study.  In the 
MCI/Prodromal population, Bayesian response adaptive randomization design is used with 
Page 1410 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 36 of 144
frequent interim analyses to continually update randomization allocation based on emerging 
clinical endpoint data.  This approach allows for ongoing assessment of drug futility or 
evidence of early success and can mitigate the risks associated with larger and longer studies 
required to demonstrate clinical efficacy by leading to more efficient study termination or 
early advancement to a Phase 3 program.  Results from this study will guide both the 
decision to move into Phase 3 development and the selection of the dose strengths to be taken 
into Phase 3.  Moreover, this study is intended to be supportive for registration in the 
MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5 mg, 15 mg and 50 mg) administered once daily (QD) for 18 months.  In the mild AD 
population, this study will compare placebo and 2 oral doses of E2609 (15 mg and 50 mg) 
administered QD for 18 months.  To date, the longest duration of dosing with E2609 is 
14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the first 60 randomized subjects have completed 12 weeks of treatment, have 
discontinued study drug or have withdrawn from the study.  The study also includes a 
number of exclusion criteria, specific blinded safety monitoring procedures and safety 
criteria for discontinuation of study drug in light of the preclinical and clinical safety data 
collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50 mg dose only, aged 65 to 
85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
Page 1411 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 37 of 144
14 days of dosing so as to assess the pharmacokinetic (PK) levels of E2609 and the 
pharmacodynamic (PD) effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  
A single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
Page 1412 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 38 of 144
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP3A4] and carboxyesterase-2 [CES2]) increased by
approximately 70% the area under the concentration × time curve (AUC) of E2609.  
Consequently, strong inhibitors of CY3A4 will be prohibited in this study.  
Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 20%) of the 
AUC of E2609.  Therefore, no restrictions are required for the use of concomitant 
medications which are known to be inducers of CYP450 enzymes.  Donepezil (a moderate 
CES2 inhibitor) caused a mild increase (by approximately 20%) of the AUC of E2609 when 
coadministered with E2609 but not when dosed at least 2 hours apart from E2609.  E2609 
(which inhibits the P-glycoprotein 1 transporter) did not affect the PK properties of digoxin.  
Nonclinical studies also indicated that other CYP pathways apart from CYP3A4 would not 
be major pathways of metabolism of E2609.  Therefore, on the basis of drug interaction 
considerations, the only restriction of concomitant medications is that for strong inhibitors of 
CYP3A4. 
Page 1413 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 39 of 144
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild AD
8.2
Secondary Objectives
The secondary objectives are:  
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the effect of E2609 compared with placebo on Aβ(1-x) in CSF after 4 weeks 
and 18 months of treatment in MCI/Prodromal subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild AD subjects
8.3
Exploratory Objectives
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after 4 weeks and 18 months of treatment in mild AD subjects
Page 1414 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 40 of 144
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during posttreatment follow-up, in 
MCI/Prodromal and mild AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b. The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d. The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during posttreatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
posttreatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
7. To characterize the population PK of E2609 in MCI/Prodromal and mild AD subjects, 
and 
to 
examine 
the 
effect 
of 
intrinsic 
and 
extrinsic 
factors 
(including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild AD subjects
Page 1415 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 41 of 144
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study 202 is a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild AD.  
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild AD, will be required for all subjects.  In addition, the MCI due to 
AD population will also be consistent with the research criterion for “Prodromal AD” in that 
episodic memory will be impaired on a list learning task (ISLT).  As the non-demented 
subjects will be consistent with criteria for both MCI due to AD and Prodromal AD they will 
be identified as MCI/Prodromal subjects in this protocol. The diagnosis of MCI/Prodromal 
AD or mild AD will be based on both clinical and biological (ie, confirmation of amyloid 
load in the brain) criteria.  
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) in MCI/Prodromal subjects, before expanding enrollment to include a larger 
population of MCI/Prodromal subjects in Stage B (maximum of approximately 500 subjects 
across both stages).  In addition, during Stage B of the study, subjects with mild AD will be 
recruited into a separate cohort (approximately 200 subjects).  All MCI/Prodromal subjects 
will be included in the primary efficacy evaluation irrespective of whether they were 
recruited into Stage A or Stage B of the study.  
Both Stage A and Stage B of the study will consist of 2 phases: Prerandomization and 
Randomization.  The Prerandomization Phase (up to 60 days) will consist of a Screening 
Visit and a Baseline Visit.  Screening assessments will be organized into 4 tiers; see 
Section 9.5.2.2, Table 6, and Figure 2.
All screening assessments must be completed, and eligibility to continue to the Baseline 
Period confirmed, before any baseline assessments commence.  Following successful 
completion of the Prerandomization Phase, eligible subjects will be randomized and will 
enter the Randomization Phase, which will consist of 2 periods: Treatment (78 weeks) and 
Follow-Up (post last dose; 12 weeks).
MCI/Prodromal subjects will be randomized to 4 treatment groups (E2609 at 3 doses or 
placebo, with an initial ratio of 1:1:1:1) and this recruitment will take place during both 
Stage A and Stage B.  Bayesian adaptive randomization will be used in Stage B in the 
MCI/Prodromal cohort.  Subjects with mild AD who are recruited in Stage B will be 
randomized to 3 treatment groups (E2609 at 2 doses or placebo).
An overview of the study design is presented in Figure 1.
Page 1416 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 42 of 144
Figure 1
Design of Study E2609-G000-202
R = randomization.
Page 1417 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 43 of 144
Stage A
Stage A of the study will be limited to approximately 25 clinical centers in the United States.  
Stage A will randomize 60 eligible MCI/Prodromal AD subjects 1:1:1:1 to 4 treatment 
groups.  There will be no Bayesian adaptation during Stage A of the study.  In addition to the 
placebo group, 3 doses of E2609 will be used to reduce CSF Aβ levels by approximately 
25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at steady state.  
PK/PD modeling shows these doses should achieve these targets when administered QD with 
food and will be confirmed or adjusted based on the 4-week assessment of CSF Aβ(1-x) (see 
Section 9.4.4).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A of the study, an independent DSMB (including at least 1 immunologist) will review 
all safety data in an unblinded manner.  The DSMB will make recommendations to Eisai 
after each review as to whether any change(s) to the study are necessary.  Unless the DSMB 
recommends otherwise, randomization of subjects into Stage A of the study will continue 
until 60 MCI/Prodromal subjects have been randomized and dosed.  
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B of the study (see Section 9.4.4).
Once 60 MCI/Prodromal subjects in Stage A have completed at least 12 weeks of treatment
(or discontinued study drug early) an interim safety analysis will be conducted by Eisai and 
the DSMB.  Subjects in Stage A will continue study drug while the DSMB reviews all the 
available safety data, but randomization of additional subjects will not take place (ie, 
recruitment into Stage B will not commence) until the safety analysis is completed by the 
DSMB.  At the time of this interim safety analysis, some subjects will have more than 
12 weeks of safety data.  
If there are safety signals with one of the E2609 dose groups that would require dose 
adjustment, changes to dose will be reflected in an amendment to the protocol. Information 
on how these subjects will be handled in the primary analysis will be described in the 
Statistical Analysis Plan.
Stage B
Stage B of the study will start after the DSMB safety review of Stage A has shown 
acceptable safety and tolerability of E2609 and after the doses of E2609 to be used in 
Stage B are confirmed.  Based on data from Stage A, the protocol will be reviewed and may 
be amended before beginning Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment in the study is 
completed; following this the DSMB will meet approximately every 6 months.
Stage B of the study will be conducted globally and will enroll, randomize, and dose up to an 
additional 440 eligible MCI/Prodromal subjects; the final total number will depend upon 
Page 1418 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 44 of 144
whether the prespecified criteria for either early success or futility are met.  In addition, a 
separate cohort of approximately 200 mild AD subjects will be randomized and dosed during 
Stage B.
Both population cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD), whereas the mild AD cohort 
will only include 2 doses of E2609 (15 mg and 50 mg QD).  
Bayesian adaptive randomization will be used in the MCI/Prodromal cohort during Stage B 
of the study.  The first 40 MCI/Prodromal subjects recruited into Stage B will be randomized 
according to a fixed schedule (1:1:1:1; placebo:5 mg E2609:15 mg E2609:50 mg E2609) and 
the remaining subjects in the MCI/Prodromal cohort will be randomized according to 
response adaptive randomizations based on the ADCOMS results using the Bayesian interim 
efficacy analyses.  The mild AD subjects will be randomized according to a fixed schedule 
(1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B of the study.
Interim efficacy analyses are planned and are discussed in Section 9.7.3.
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days and a window of 7 to 10 days is to be 
observed between the completion of all Baseline Visit assessments and randomization into 
the study at Visit 3.  Thus, the Prerandomization Phase will last for up to 60 days.  The series 
of assessments conducted during this phase will determine eligibility for randomization into 
the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization the clinician will provide a judgment on the classification of a subject as either 
MCI/Prodromal (eligible for Stage A and Stage B) or likely mild AD (eligible for Stage B 
only).  This judgment may be discussed and reviewed with the Sponsor or Sponsor’s 
representative, as necessary.
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
Page 1419 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 45 of 144
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.
Every effort should be made to conduct these assessments in the morning, but if this is not 
possible, they should be conducted at the same time of day at all subsequent visits.  The 
screening assessments/procedures have been organized into 4 distinct tiers (Table 6 and
Figure 2).  All assessments/procedures in each tier should be completed, and eligibility to 
continue screening in the study confirmed, before any assessments/procedures from the next 
tier commence.  
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) 
at Screening.  The investigator will determine whether the caregiver or informant must attend in person or whether 
telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other 
factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).
Page 1420 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 46 of 144
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days.
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination will be 
performed.  A urine pregnancy test will be conducted for females of childbearing potential.  
Blood will be collected from all subjects for clinical chemistry and hematology, lymphocyte 
subset analyses, Ig analyses, and PD assessments.  Blood samples will be collected and 
stored for determination of a subject’s previous exposure to infective pathogens in the event 
of AEs that warrant further investigation occurring at a later point in the study.  Psychometric 
assessments will be administered to the subject in the order stated in Table 6.  The caregiver 
or informant needs to be present at this visit.  The Columbia Suicide Severity Rating Scale 
(C-SSRS) will also be administered (Section 9.5.1.5.11).
CSF will be obtained at this visit for PK and PD assessments (see Section 9.5.1.5.3).  
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase within 7 to 10 days following completion of the Baseline Visit 
assessments.
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Safety criteria for discontinuation of study drug are detailed in Section 9.3.3.
Page 1421 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 47 of 144
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
9.1.2.3
Follow-up Period
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and will end on or before Aug 2019.

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild 
AD to determine whether the effects of E2609 in this later stage population are comparable 
with those established in the MCI/Prodromal population within this same study (see 
Section 9.2.3 for discussion of the Bayesian design used in this study).  
Page 1422 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 48 of 144
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and with the definition of Prodromal AD per 
Dubois et al., 2010 (see Section 9.2.2).  
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of well 
established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (see Section 9.2.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; an amyloid 
biomarker, which is the change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months 
of treatment in MCI/Prodromal subjects; and a cognitive and functional assessment, which is 
the change from baseline in the derived ADCOMS at 18 months of treatment in mild AD 
subjects.  Exploratory endpoints including assessments of efficacy, safety and other 
biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
The rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain has already reached a plateau and significant neurodegeneration has occurred 
(Jack, et al., 2010).  There is a growing consensus within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  It is possible that this consideration explains the failure of the 
humanized
monoclonal antibody bapineuzumab (which targeted brain amyloid) to 
demonstrate clinical efficacy in late-phase studies in mild-to-moderate AD dementia.  
The primary patient population of focus in this study is subjects with MCI/Prodromal AD
and they will be recruited during both Stage A and Stage B of the study.  The mechanism of 
action of a BACE1 inhibitor where amyloid production is reduced means E2609 is more 
likely to be efficacious (ie, slow disease progression) the earlier in disease progression 
treatment is started, where limited neurodegeneration has occurred and associated clinical 
deficits are at a minimum.  Key safety aspects will be assessed in Stage A in which the 
Page 1423 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 49 of 144
MCI/Prodromal AD subjects have less advanced disease compared with subjects with mild 
AD who will also be recruited in Stage B.  
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with slightly more advanced disease 
such as mild AD.  A study of tarenflurbil, a selective Aβ(1-42)-lowering agent, on cognition 
and function in subjects with mild to moderate AD showed only the subjects with mild AD
had lower rates of decline than those in the placebo group in activities of daily living and 
global function; however, slowing of cognitive decline did not differ significantly 
(Wilcock, et al., 2008).  Similarly, differential effects on cognitive measures have been 
observed with solanezumab, where some benefit from treatment was observed in subjects 
with mild AD but not in subjects with moderate AD, although studies with solanezumab 
were considered to have failed to improve cognition or functional ability significantly 
(Doody, et al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor 
E2609 in 2 different subject populations that differ in terms of AD severity before the 
initiation of large Phase 3 clinical studies.
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild AD recruited in Stage B will be assessed as a “nested” population that 
does not follow the Bayesian adaptive design.  It was not considered appropriate to have a 
Bayesian design for both cohorts as this would have substantially increased the overall study
sample size, delayed analyses of dose response, and would have added background “noise”
for the comparison of subjects with MCI/Prodromal AD compared with those with mild AD. 
Data from each cohort will be analyzed independently for the purposes of decision making.  
A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild AD 
confounding the results for the primary population (MCI/prodromal).  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
Page 1424 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 50 of 144
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the episodic memory impairment that characterizes MCI 
with high amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle 
Flagship Study of Ageing study).  Data are robust across different groups of healthy older 
individuals, and accordingly criteria used for defining abnormal performance are reliable
(Thompson et al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate 
Page 1425 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 51 of 144
that the ISLT will be sensitive to the expected changes in amyloid-related memory 
dysfunction with E2609 treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility 
inclusion criterion)

To evaluate safety (principally by magnetic resonance imaging [MRI])

To confirm a PD effect in terms of both Aβ in CSF and brain amyloid assessed by 
PET and to establish that this PD effect is maintained long-term

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both total tau (t-tau) and p-tau are sensitive markers of axonal and neuronal degeneration 
(t-tau) and neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel 
with disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have 
been correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful 
predictors of cognitive decline and progression to dementia due to AD.  Rebalancing 
dysregulated amyloid production early in the process may positively affect the 
neurodegenerative process and thus affect these markers and benefit the disease trajectory.  
Therefore, monitoring these markers in conjunction with amyloid imaging may provide 
further supportive evidence of efficacy.  
Page 1426 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 52 of 144
Baseline levels of Aβ(1-42), tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be performed in this study for 2 primary reasons: 1) to confirm 
the presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild AD
at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels in the brain, 
both by whole brain analysis (the average of 5 to 6 cortical regions) and brain region 
analysis.
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted until 18-month PET scans of acceptable quality have been obtained for at 
least 25 subjects per treatment arm for each amyloid PET ligand used.
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the Mild AD population).  A large body of data has shown that 
structural MRI reliably tracks disease progression in AD.  Atrophy tends to occur 
preferentially in the lateral temporal and posterior parietal regions during the early stages of 
disease and progresses towards the anterior regions of the brain (frontal cortex) in its later 
stages.  Clinically efficacious doses are predicted to be associated with a slowing in the rate 
of hippocampal atrophy compared with rates observed in the placebo and non-efficacious 
dose groups.  Treatment effects on left and right hippocampal, whole brain, and total 
ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as mild AD-dementia.  Lower levels of 
CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF tau in addition to 
the presence of the ApoE4 allele have all been associated with greater rates of brain atrophy 
(Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in various analyses.  
Hippocampal atrophy has also been shown to predict clinical progression independently of 
Page 1427 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 53 of 144
amyloid levels in the brain (Jack, et al., 2010), and this measure will be entered as a covariate 
in the analysis of the clinical endpoints along with the aforementioned variables.  
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Two-stage study design:  there will be a pause in recruitment after 60 MCI/Prodromal 
subjects have been randomized to study drug (Stage A).  Only after the safety of 
E2609 in these first 60 subjects (consisting of up to 12 weeks data for the later 
subjects and longer dosing periods for the earlier subjects) has been reviewed by the 
DSMB and considered acceptable, will randomization of further subjects into the 
study commence (Stage B).

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety criteria for discontinuation of study drug based on CD4 (T helper cells), CD8
(cytotoxic T cells), CD19 (B cell) and other lymphocytes (absolute counts and 
percentage change from baseline), skin rash, reoccurrence of herpes virus infections 
including any oral herpes, genital herpes or shingles, other infections, MRI changes, 
ECGs, and pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course 
of the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of
vital signs, regular ECGs, physical and neurological examinations, and centralized 
dermatological assessments (via photography) at regular intervals.  AEs that might 
indicate signals of possible drug abuse potential will require a detailed follow-up.  
Subjects reporting AEs relating to abnormal dreams, nightmares, or sleep terror will 
Page 1428 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 54 of 144
be questioned on the frequency and impact of these events.  To assess potential 
immunomodulatory effects, peripheral blood mononuclear cells (PBMCs) will be 
collected at baseline, during treatment, and posttreatment.  
As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur with 
BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to date, 
assessments by a reviewing dermatologist will be performed at regular intervals during the
study.  These assessments will be made centrally, using standardized photography and will 
specifically include evaluation of any areas of depigmentation or any rash.  Dermatological 
assessments will be supplemented with a specific question to subjects regarding skin changes 
at each visit.  Any such changes could be referred to the central reviewing dermatologist, and 
to a local dermatologist if needed, for further evaluation.  See Section 9.5.1.5.8 for further
details.

Baseline and on-study blood, DNA, and CSF samples will be taken and stored for all 
subjects.  These samples may be tested in the event that a subject develops AEs that 
warrant further investigation (eg, if a subject develops a treatment-emergent 
infection) (see Section 9.5.1.2.2).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Treatment Phase of the study, and at the final Follow-Up Visit.

Full neurological examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  Details of the neurological 
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using 
the detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, 
Baseline, and at regular intervals during the Treatment Phase and Follow-Up periods 
of the study (see Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 2 off-treatment Follow-Up
visits (4 and 12 weeks after the last dose of study drug).  More frequent safety 
assessments can be made as unscheduled assessments/visits during the off-treatment 
Follow-Up period, if clinically indicated.

An ophthalmic examination will be conducted at Baseline and if the subject 
experiences visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will randomize 60 eligible MCI/Prodromal subjects at 25 centers in the United 
States.  Stage B will randomize up to an additional 440 eligible MCI/Prodromal subjects at 
approximately 125 centers globally; the final total number will depend upon whether the 
Page 1429 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 55 of 144
prespecified criteria for either early success or futility are met.  In addition, a separate cohort 
of approximately 200 mild AD subjects will be randomized and dosed during Stage B.
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
(Stage A and Stage B) or mild dementia (Stage B only) and also complies with the 
following:  
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤20
d.
MMSE ≥20
2. Amyloid positive PET image based on centralized PET scan reading 
3. Male or female, age 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. If receiving acetylcholinesterase inhibitor (AChEIs) or memantine, must have been on a 
stable dose for at least 12 weeks before the Baseline cognitive assessments at Visit 2, 
with no plans for dose adjustment in the foreseeable future.  Treatment-naïve subjects can 
be entered into the study but there should be no plans to initiate treatment with AChEIs or 
memantine at the time of entry into the study.
Page 1430 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 56 of 144
6. Must have been on stable doses of all other permitted chronically used concomitant 
medications (ie, not related to their cognitive decline) for at least 4 weeks before 
randomization
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (eg, arachnoid cysts) or brain tumors (eg, meningioma).
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild AD diagnosis or could 
interfere with study assessments or procedures 
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 (<LLN) levels for the testing laboratory (if subject is 
taking vitamin B12 injections, level should be at or above the LLN for the testing 
laboratory) at Screening 
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Subjects with hepatic impairment, with total bilirubin greater than 1.5×upper limit of 
normal (ULN) or International Normalized Ratio (INR) greater than 1.7 at Screening or
Baseline.  Subjects with Gilbert’s syndrome need not be excluded.
11. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
Page 1431 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 57 of 144
12. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
13. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
14. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
15. Subjects with chronic viral hepatitis
16. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
17. A history of ophthalmic shingles
18. A history of ocular herpes simplex virus (HSV) infection
19. Any live vaccine in the 3 months before randomization.  
20. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR, etc) must be repeated.
21. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
22. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
23. Ig (IgG, IgA, or IgM) levels below the LLN
24. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
25. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
26. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
27. Left bundle branch block at Screening or Baseline 
28. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
Page 1432 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 58 of 144
29. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
30. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
31. Type 1 or Type 2 diabetes mellitus that is not well controlled
32. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
33. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
34. Hypopigmentation conditions (eg, albinism and vitiligo)
35. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive in the urine drug screen need not be excluded if in the clinical 
opinion of the investigator, this is due to the subject taking prior/concomitant medications 
for a medical condition that is not exclusionary and not due to drug abuse.   
36. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
37. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
38. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
39. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
40. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
41. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
42. Females who are lactating or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Page 1433 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 59 of 144
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
43. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study treatment period or 
for 28 days after study drug discontinuation.

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study treatment period or for 28 
days after study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing or who do not agree to use 
the same contraceptive during the study treatment period or for 28 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]).
44. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
not practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 28 days after study drug discontinuation.
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may discontinue study drug or withdraw the subject from the study at any 
time for safety or administrative reasons.  The subject may decide to stop study drug or 
withdraw from the study at any time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 4 and 12 weeks after the last dose of study drug (see Section 9.1.2.3).  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at 
Visits 11, 14, 15, 16, 17, and 18, if these visits have not already been performed).  At these 
visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) 
will be conducted.  Regularly scheduled clinical efficacy visits do not need to be attended if 
they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days 
of either of the Follow-Up Visits (Visit 19 and Visit 20).  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled 
clinical efficacy visits as outlined above. 
Page 1434 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 60 of 144
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related criteria for discontinuation of study drug include the following:  
a.
A study drug discontinuation threshold will be set based on absolute counts of CD4 (T 
helper cells), CD8 (cytotoxic T cells), or CD19 (B cells).  The discontinuation threshold 
will be set at below the level of the LLN, at a level that represents a greater risk of 
opportunistic infection in the treated population.  For CD4 (T helper cells) the 
discontinuation threshold is 250 cells/µL.  For CD8 (cytotoxic T cells) and CD19 (B 
cells) the discontinuation thresholds are 150 cells/µL and 50 cells/µL, respectively.  Any 
subject who has CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) 
absolute counts below the discontinuation threshold as confirmed by a repeat test 
conducted within 1 week of the initial test will be discontinued from study drug.
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the LLN and the discontinuation threshold will have lymphocyte subset
counts performed on a weekly basis.  Subjects with a >33% reduction from baseline in 
CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts will also 
have lymphocyte subset counts performed on a weekly basis.  For these subjects, the 
decision as to whether the subject remains on study drug or is to be discontinued from 
study drug will be based upon clinical judgment and will take into account any clinical 
presentation in addition to the lymphocyte subset counts.  These subjects may continue 
with treatment if there is no clinical evidence of infection.  They will be discontinued 
from study drug if they have infections of a moderate to severe intensity (eg, subjects 
whose infections are not localized, or are systemically unwell, or who require systemic 
antiinfective drug treatment).
Table 1
Study Drug Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Decision to continue or 
discontinue
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
discontinuation threshold
Retest within 1 week
If retest performed within 
1 week confirms lymphocyte 
subset counts below the 
discontinuation threshold, 
discontinue study drug
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts between LLN and 
discontinuation threshold or >33% reduction from 
baseline in CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts
Lymphocyte subset counts to be 
performed weekly until counts 
return to ≥ LLN or no more 
than 33% reduction from 
baseline
Decision will be based upon 
lymphocyte subset counts and 
clinical judgment
LLN = lower limit of normal.
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
Page 1435 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 61 of 144
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
discontinuation thresholds, study drug will be discontinued.  All subjects with severe 
infections will be discontinued from study drug.  All subjects with herpes zoster 
(shingles) or ocular herpes infections will be discontinued from study drug, regardless of 
severity of presentation.  Subjects with mild or moderate infection may continue 
treatment with study drug unless otherwise clinically indicated or otherwise specified 
below.  Specifically, when any of the CD4 (T helper cells), CD8 (cytotoxic T cells), and 
CD19 (B cells) absolute counts are between the LLN and the discontinuation thresholds 
or have shown >33% reduction from baseline, subjects with infections of moderate 
intensity will be discontinued from study drug (eg, subjects whose infections are not 
localized, or subjects who are systemically unwell, or who require systemic antiinfective 
drug treatment).  All subjects with infection who are discontinued from study drug will 
be followed for a period of 12 weeks or until the infection resolves/ stabilizes or until the 
CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts have 
returned to >LLN (whichever comes latest).
Table 2
Study Drug Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
Mild
Moderate
Severe
CD4 (T helper cells), CD8 (cytotoxic T cells),
or CD19 (B cells) absolute counts below 
discontinuation threshold
Discontinue study 
drug
Discontinue study drug
Discontinue study 
drug
CD4 (T helper cells), CD8 (cytotoxic T cells),
or CD19 (B cells) absolute counts between 
LLN and discontinuation threshold or >33% 
reduction from baseline in CD4 (T helper 
cells), CD8 (cytotoxic T cells), or CD19 
(B cells) absolute counts
May continue 
treatment with study 
drug unless clinically 
indicated
Discontinue study drug
Discontinue study 
drug
CD4 (T helper cells), CD8 (cytotoxic T cells), 
or CD19 (B cells) absolute counts always 
>LLN and no reduction from baseline >33%
May continue 
treatment with study 
drug unless clinically 
indicated
May continue 
treatment with study 
drug unless clinically 
indicated 
(See (e) for exception)
Discontinue study 
drug
LLN = lower limit of normal.
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
e.
Subjects who develop moderate to severe oral or genital herpes should be discontinued 
from study drug.  Subjects who develop a mild case of oral or genital herpes may remain 
on study drug even if the event lasts more than 72 hours.
Page 1436 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 62 of 144
f.
Development of any of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 4 and 12 weeks after the last dose of 
study drug.  They will also undertake an Unscheduled Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
be performed at approximately the time of the second Follow-Up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages as detected by MRI, but none of the features which merit 
discontinuation of treatment (ie, vasogenic edema, macrohemorrhage, an area of 
superficial siderosis, or a symptomatic treatment-emergent microhemorrhage) may 
continue with treatment.  These subjects will have safety assessments (including MRI) at 
approximately 4 weeks after the visit at which such MRI features were found.  They will 
also continue with the scheduled MRI scans.  Additional unscheduled MRI scans may be 
arranged on an individual subject basis in discussion with the study medical monitor.
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to
be administered orally, QD, with food.  As shown in Figure 1, there will be 4 treatment arms
in the MCI/Prodromal Cohort where E2609 will be administered at 3 doses (5 mg, 15 mg and 
50 mg) and the comparator is placebo.  In the Mild AD Cohort, there will be 3 treatment 
arms where E2609 will be administered at 2 doses, and the comparator is placebo.  The 
2 highest E2609 doses (15 mg and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A for the MCI/Prodromal group, will be used for the Mild AD population.
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Section 9.3.3 for safety-related discontinuation criteria of study drug.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
Page 1437 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 63 of 144
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5 mg, E2609 15 mg, E2609 50 mg, or 
placebo.  The tablets will be supplied by the Sponsor in labeled blister packs.  The product 
release certificates for E2609 and placebo will be included in the clinical study report for this 
protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name and Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
Page 1438 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 64 of 144
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for MCI/Prodromal subjects and for mild AD subjects are described in Section 9.4.1.
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5 mg, 15 mg, and 50 mg QD administered as the tablet formulation with food in this 
study should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% 
at steady state, respectively (Table 3).
Page 1439 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 65 of 144
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1
Activity
% Reduction 
CSF A(1-x)
5
6.2
3.3
80.3
16.2
33
15
18.6
10
240.9
36.6
56
50
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = Beta-amyloid converting enzyme, CSF = cerebrospinal fluid,  Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013). Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and Mild AD dementia patients.
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 400 mg (17.3% 
decrease).  No subjects had infections or drug rash while receiving E2609 100 mg QD or at 
lower doses in Study 002, whereas at 200 mg and 400 mg QD, 4 subjects had symptomatic 
orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The highest dose 
for Study 202 of 50 mg QD (tablet administered with food) is therefore expected to have a 
similar or better safety profile compared with the 100 mg QD capsule (administered fasted) 
in Study 002.  Specific exclusion criteria, blinded and unblinded safety monitoring 
procedures, and safety criteria for discontinuation from study drug are included in this study
in order to mitigate any immunology-related risk with E2609, particularly in light of the 
progression from 14 days of dosing (Study 002) to 18 months of dosing in this study.
Subjects in the MCI/Prodromal cohort, whether in Stage A or Stage B, will be randomized to 
receive either placebo or E2609 at 5 mg, 15 mg, or 50 mg QD.  Subjects with mild AD
(Stage B) will be randomized to receive either placebo or E2609 at 15 mg or 50 mg QD, but 
not the 5-mg QD dose.  The rationale for not including an E2609 5-mg QD dose in the dose 
regimens for subjects with mild AD is that more advanced disease may require greater 
reduction in CSF Aβ levels for comparable effects. 
Page 1440 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 66 of 144
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B, where PD is measured as reductions from baseline in CSF Aβ(1-x) 
levels.  If the 95% confidence interval of the mean percentage change from baseline in CSF 
Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 does not include its 
intended target value (ie, 25%, 50%, and 75% reductions from baseline, respectively for 
E2609 at 5 mg, 15 mg, and 50 mg), PK/PD modeling will be conducted.  This PK/PD 
modeling will use the observed PK and PD data from Stage A and will relate the average 
steady state plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction 
from baseline after 4 weeks of dosing.  From this model, the new target plasma steady state 
concentrations of E2609 required to achieve the target levels of CSF Aβ(1-x) reduction will 
be estimated again.  Dose adjustment for Stage B may be considered if it is possible to get 
closer to the new target plasma steady state concentrations of E2609 required to achieve the 
intended target levels of CSF Aβ(1-x) reduction than is possible with the initially planned 
doses, given the limitation that E2609 dose adjustments will have to be in 5-mg increments 
or decrements.  Subjects already randomized to a dose that needs to be adjusted will be 
switched to the new adjusted dose and complete their treatment at this new dose.
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects and all personnel involved 
with the conduct and interpretation of the study, including investigators, site personnel, and 
Eisai staff will be blinded to the treatment codes (double-blind).  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments (ie, those who are trained and certified to perform the various cognitive 
assessments that are undertaken in this study).  Furthermore, at the site, the notes and reports 
relating to safety assessments must be kept separate from the notes and reports relating to 
efficacy.
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
The PK/PD interim analysis to confirm the E2609 doses to be used for Stage B will be 
conducted by an independent group.  Any changes to dose will be reflected in an amendment 
Page 1441 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 67 of 144
to the protocol and the Statistical Analysis Plan will detail how data will be handled in the 
primary analysis.  
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Listings of prohibited and permitted drugs are provided in Appendix 2. 
Prohibited 
medications are presented in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and
Listing 6.  Medications that are permitted with restrictions are listed in Listing 7, Listing 8, 
and Listing 9.
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives 
or 7 days (whichever is longer) before randomization 

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-
lives or 14 days (whichever is longer) before randomization 

Strong CYP3A4 inhibitors are not permitted for a period of 5 half-lives or 14 days 
(whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not 
permitted for a period of 5 half-lives or 60 days (whichever is longer) before 
randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 
Page 1442 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 68 of 144

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for 
medications that are administered as short courses of treatment or which are to be 
used intermittently as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not 
permitted during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Phase of 
the study.  CRAs will review treatment compliance during site visits and at the completion of 
the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
Page 1443 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 69 of 144

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of 
the principal investigator’s current medical license (required for United States sites) 
or medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, and (e) documentation of 
returns to the sponsor.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs 
and empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and, together with unused study drugs that were shipped to the site 
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 
Page 1444 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 70 of 144
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness,
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
Page 1445 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 71 of 144
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
9.5.1.2.2
VIRAL TESTING
As specified in Table 6, blood will be collected for screening for Hepatitis B and Hepatitis C 
for determining eligibility, and at Baseline for viral characterization. 
9.5.1.2.3
B12 TESTING
Blood will also be collected for vitamin B12 levels as specified in Table 6.
9.5.1.2.4
TB EXPOSURE TESTING
Blood will also be collected for testing for previous TB exposure, as specified in Table 6.  
9.5.1.2.5
URINE DRUG TESTING
Urine will be collected for drug screening as specified in Table 6.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT 
(immediate recall), CBB, and ISLT (delayed recall) at Screening; and MMSE, CDR, 
ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) at the Baseline 
Visit.
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild AD.  It also shows sensitivity to treatment 
effects with AChEIs.  The ADCOMS assesses both cognitive and functional domains and can 
be offered as a single primary clinical endpoint.  The ADCOMS has a range from 0 to 1.97.  
Page 1446 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 72 of 144
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test where the subject presses a key when the card 
is turned face up from a pack of cards (“Has the card turned over”).  Speed of 
response is the measure.
2. Identification – a simple choice reaction time test where the subject presses 1 of 2
keys when the card just turned face up is either a red card or a black card (“Is the card 
red”).  Speed of response is the measure.
3. One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial 
or not (“Is the previous card the same”).  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not 
in the task (“Have you seen this card before in this task”).  Accuracy of response is 
the measure.
ISLT: The ISLT is a verbal learning and episodic memory test assessing both immediate 
and delayed recall.  Subjects are read a list of 12 items that can be obtained at the local 
shopping center.  Subjects are asked to recall as many of the items as possible and this 
immediate recall trial is repeated 3 times.  After a delay of approximately 15 minutes, in 
which time the CBB is performed, subjects are again asked to recall as many of the words on 
the shopping list as they can (ie, a delayed recall trial).  
Mini Mental State Examination: A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:
The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire:
Either a caregiver or informant or the subject 
provides performance ratings (from 0 to 3) on 10 complex activities of daily living performed 
within the preceding 4 weeks.  Scores range from 0 (independent) to 30 (dependent).  
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
Page 1447 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 73 of 144
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
CSF samples will be collected by LP (gravity drip method) at the timepoints specified in 
Table 6 and Table 7.  The CSF sample taken at the Baseline Visit will only be performed 
after confirmation of an amyloid positive PET scan. See Section 9.5.1.4.2  for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed, depending on emerging 
data from other studies with E2609.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug 
with food at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or 
at the ED Visit) the PK blood sample should be collected shortly after completing the LP.
Although the PK sampling procedures at the ED visit should follow those of Visit 18, in the 
event that study drug has already been discontinued prior to the ED visit, then no dosing will 
be conducted. However, a PK sample at trough (before LP) will be collected, followed by LP 
Page 1448 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 74 of 144
at approximately the same time as previous visits, and then the post-LP PK sample will be 
collected. 
Blood will also be drawn where possible at the first report of an SAE or severe unexpected 
AE and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  At Baseline, a CSF sample will be collected by LP (gravity drip method) after 
fasting (preferred), or at least 2 hours after the most recent meal.  The timing of the Baseline 
LP needs to be scheduled carefully such that subsequent LPs (Visit 7 and Visit 18) can be 
performed between 4 and 8 hours postdose and at a similar time of day (±1 hour) for each 
individual subject.  At visits where cognitive tests are also performed, the LP must be 
performed after the cognitive tests have been completed; the subjects should rest and drink 
some fluid to hydrate after the cognitive tests and before the LP.  The CSF sample will not be 
taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample.  The CSF 
sample will be used for PD assessments including but not limited to CSF Aβ(1-x), Aβ(1-42), 
t-tau, p-tau, and BACE.  The plasma sample will be used for Aβ(1-x) analysis and may be 
used for exploratory biomarker analyses (eg, miRNA).  Aβ(1-x) in both CSF and plasma will 
be measured using a commercially based enzyme-linked immunosorbent assay (ELISA).  
The pre- and post-screening analysis of CSF Aβ(1-42), t-tau, and p tau will be performed 
using ELISAs.  BACE1 levels will be measured using internally developed fluorescence 
resonance energy transfer and ELISA based assay(s).  Substrates of BACE1 inhibition may 
also be explored using Western blots or other amenable methodology if clinical observations 
warrant and if analytes can be reliably tested in samples collected.
The blood sample collected for PD analyses at Baseline should be collected shortly after 
completing the LP at Baseline.  The sample should be collected at fasting or at least 2 hours 
after the most recent meal.  
At the Baseline Visit, CSF and blood samples will be collected and stored for determination 
of prior exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
Testing may include, but not be limited to, serological tests, viral titer by quantitative 
polymerase chain reaction, or human leukocyte antigen genotyping.
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.4.2 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any collected CSF 
samples will be stored for up to 15 years.  
Page 1449 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 75 of 144
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Pharmacogenomics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous E4 versus non-E4) and the NAT2 phenotype of 
subjects enrolled in this study.  The findings will be used in the statistical analysis to 
determine the effects on treatment response, safety, or PK of E2609.
Details of which 
genotype / phenotype data will be applied to the analyses of efficacy, safety or PK will be 
discussed in the Statistical Analysis Plan. 
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  Longitudinal amyloid PET imaging will also be conducted after 18 months of 
treatment (or at ED, providing the subject has received at least 39 weeks of study drug).  
Longitudinal amyloid PET imaging will only be conducted until acceptable 18-month PET 
scans have been obtained for at least 25 subjects per treatment arm for each amyloid PET 
ligand used (Table 6).  PET scanning will be performed with a locally approved Aβ imaging 
agent, eg, Amyvid. Descriptions and detailed instructions for all imaging can be found in the 
imaging manual.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; centralized dermatological assessments; the C-SSRS; and safety MRIs as 
detailed in Table 6 and Table 7.  will also be conducted.  Peripheral blood mononuclear cells 
(PBMCs) will be collected at Baseline, during treatment, and posttreatment for exploratory 
immunomodulatory and immune-based analyses.
Page 1450 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 76 of 144
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments (see Section 9.4.6).
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  It is not 
necessary to report every sign or symptom as a separate AE if the overall disease 
[diagnosis] is being reported as an AE.)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, discontinuation of study 
drug, or withholding of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  For subjects 
who discontinue early from study drug but undertake further efficacy assessments, AEs will 
only be collected for 3 months after the last dose of study drug, ie, through to the second 
follow-up visit (Visit 20).  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure reported on the Screening Disposition eCRF.  SAEs will be 
collected for 3 months after the last dose of study drug, ie, through to the second follow-up 
visit (Visit 20).  For subjects who discontinue early from study drug but continue with further 
efficacy assessments, SAEs will be solicited only for 3 months after the last dose of study 
drug, i.e. up to the 2nd follow up visit (Visit 20). However, any SAEs volunteered by 
subjects after this time point must be reported according to standard procedures.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Page 1451 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 77 of 144
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADCOMS, ADAS-cog14, MMSE, and CBB 
(see Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment 
Period, and if this cognitive decline is considered by the investigator to be excessive relative 
to the subject’s recent AD history, this finding should be reported as an AE.
AEs that might indicate signals of possible drug abuse potential will require a more detailed 
follow-up through completion of a specific eCRF form.  This includes AEs that fall into the 
following categories and examples of such AEs are provided in Appendix 4

Euphoric mood  

Elevated mood  

Feeling abnormal

Feeling drunk

Feeling of relaxation

Thinking abnormal 

Hallucination

Inappropriate affect

Mood disorders and disturbances

Drug tolerance

Psychosis

Dissociative state
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
The following adverse events will require the collection of information sufficient to provide a 
detailed description of the event, treatment and outcome to the Medical Monitor for the 
study: any treatment-emergent significant laboratory abnormality; any seizures, herpes zoster 
infection, severe infection; any moderate to severe drug rash or any rash lasting more than 
72 hours (regardless of severity); amyloid-related imaging abnormalities (vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a new microhemorrhage); a “yes” 
answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  
Page 1452 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 78 of 144
All AEs must be followed through the second follow-up visit (Visit 20), or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study 
treatment

The course of the event, especially the effect of discontinuation of study treatment 
or reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with 
other similar treatments

The presence of risk factors in the study subject known to increase the occurrence 
of the event

The presence of nonstudy, treatment-related factors that are known to be 
associated with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
Page 1453 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 79 of 144
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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.  
For this study, the following events should always be considered serious and reportable using 
the criteria of important medical event if the event does not meet other serious criteria:  new 
onset seizures, ocular herpes.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the eCRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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
Page 1454 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 80 of 144

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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety criteria for discontinuation from study drug related to absolute 
counts of CD4, CD8, and B lymphocytes, and for lymphocyte subset counts.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils), and 
(Screening and Beseline only), PT, PTT, and INR
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte subset analyses (see Table 5).  Regulatory T cells will be measured using 
CD4, CD25, and CD127 cell surface markers and FoxP3 intracellular marker.  
PBMCs
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HBsAg [Hepatitis B]).
Viral characterization (including HSV1, HSV2 and CMV, etc)
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function (thyroid stimulating hormone, free triidothyronine and free 
thyroxine) and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
CMV = cytomegalovirus, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV = herpes 
simplex virus, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood mononeuclear cell,
PT = prothrombin time, PTT = partial thromboplastin time.
The 8 different surface markers (CD3, CD4, CD8, CD45, CD19, CD16, CD56, and CD14) 
and total lymphocyte counts will be measured in order to provide the lymphocyte subset data 
as shown in Table 5.  In addition, Regulatory T cells will be measured using CD4, CD25, and 
CD127 cell surface markers and FoxP3 intracellular marker.  
Page 1455 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 81 of 144
Table 5
Lymphocyte Subtyping 
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the
visits designated in Table 6 and Table 7 by a validated method.  Measurements of sitting BP
and heart rate will be obtained.  All BP measurements should be performed on the same arm, 
preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
in the supine position for at least 5 minutes.
Page 1456 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 82 of 144
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2* Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.
MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging 
should be conducted within the 7 days before Visits 14, 16, and 18 and at the second 
Follow-Up Visit (Visit 20).  In the event of an Unscheduled Visit, the investigator in 
consultation with the sponsor will determine whether or not a safety MRI should be 
conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed 
during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and Follow-Up Visits at 4 weeks and 12 weeks 
after the last dose of treatment.  Subjects will also undertake an Unscheduled Visit (with 
MRI) at approximately 30 days after the visit at which such MRI features were first 
Page 1457 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 83 of 144
identified.  Additional visits may be arranged if clinically indicated in the opinion of the 
investigator, and may occur later than 12 weeks after the final dose of study drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Centralized skin assessments, using standardized photography, will be conducted by a 
reviewing dermatologist at the times shown in Table 6 and Table 7.  These assessments will 
specifically include evaluation of any areas of depigmentation or any rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the clinical database.  Physical 
examination may
be undertaken where indicated.  Treatment-emergent abnormal 
dermatological findings should be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve.  Treatment-emergent abnormal neurological 
findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Phase, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 1458 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 84 of 144
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.4.2, CSF, blood, and DNA samples will be collected and may be 
used for exploratory biomarker analyses, as well as tested in the event that a subject develops 
AEs that warrant further investigation.  
9.5.1.5.13
OPHTHALMIC EXAMINATIONS
An ophthalmic examination will be conducted at Baseline (unless the subject has had a 
comprehensive eye exam within the past 12 months, from which a report is available).  An 
additional examination will be conducted, if the subject experiences visual disturbances 
during the course of the study or is medically indicated.  The ophthalmic examinations
should include fundoscopy to look at the optic disc, macula and the rest of the retina, as well 
as an assessment of visual acuity and visual fields.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the Schedule of Procedures/Assessments for the Randomization Phase.
Page 1459 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 85 of 144
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Period
Screening
Baseline
Visit
1
2
Procedures/ Assessments (to be completed in a maximum of 50 days)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Demographics
X (Tier 1)
Medical historya
X (Tier 1)
Prior / concomitant medicationsb
X (Tier 1)
X
Vital signs including weightc 
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTd
X (Tier 1)
X
MMSEd
X (Tier 1)
X
CDRd
X (Tier 1)
X
FAQd
X (Tier 1)
X
ADAS-cog14d
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGe
X (Tier 2)
X
Blood and urine for clinical laboratory testsf
X (Tier 2)
X
Blood for lymphocyte subset analysesg
X (Tier 2)
X
Blood for Ig analysesh
X (Tier 2)
X
Blood for viral screeni
X (Tier 2)
Blood for thyroid function testsj
X (Tier 2)
Blood for vitamin B12 test
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIk
X (Tier 3)
Amyloid PET scanl
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagem
X
Blood sample for PK assessmentsn
X
Blood sample for PD and exploratory biomarker assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Blood sample for PBMC isolation
X
Blood sample for viral characterizationq
X
Centralized dermatological assessment via photographyr
X
Neurological examinations
X
Ophthalmic assessmentt
X
Page 1460 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 86 of 144
Notes for Table 6
AchEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CMV = 
cytomegalovirus, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = 
electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the Functional Activities Questionnaire), 
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HSV1 = herpes simplex virus 1 (orolabial 
herpes), HSV2 = herpes simplex virus 2 (genital herpes), Ig = immunoglobulin, INR = Inernational Normalized Ratio, 
ISLT = International Shopping List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental 
State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = 
pharmacodynamics, PK = pharmacokinetics, PET = positron emission tomography, PT = prothrombin time, PTT = partial 
thromboplastin time,TB = tuberculosis.
Note:  Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each 
tier should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence.  Similarly, all screening assessments and procedures must be completed, and eligibility to continue in 
the study confirmed, before any baseline assessments and procedures commence.  Adverse events and eligibility against
inclusion and exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  
Note:  All screening and baseline assessments are to be completed within 50 days.  The interval between availability of the 
results of the last screening assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as 
possible and ideally should not exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur 7 to 10 days after 
completion of the Baseline visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is 
required to take Exclusion Criterion #19 into account.  Thus, the total Prerandomization Phase may be up to 60 days.
a:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  
b:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
c:
Weight, respiratory rate, body temperature, and sitting blood pressure and heart rate will be obtained.  
d:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws).  
The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, ISLT (delayed recall), and CBB 
(repeat CBB for additional practice) at Screening; and MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), 
CBB, and ISLT (delayed recall) at the Baseline Visit.  At visits where the CDR or FAQ are conducted, the 
investigator will determine whether the caregiver or informant must attend in person or whether telephone contact 
will be suitable, and will base this determination upon the functional ability of the subject among other factors.
e:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
f:
Clinical laboratory tests consist of hematology (including PT, PTT, and INR), clinical chemistry, and urinalysis.
g:
Lymphocyte subsets to be measured include CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), 
CD16/CD56 (natural killer cells) and CD14 (macrophages).  Regulatory T cells will also be measured (CD4, CD25,
and CD127, FoxP3).  Viability staining may also be employed.
h:
Igs to be analyzed include IgG, IgA and IgM.
i:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
j:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine and free thyroxine.
k:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images in addition to sequences for resting state functional MRI.  
MRI will be read by an approved central reader.  Volumetric MRI for PD assessment will be performed in all subjects 
immediately following the safety MRI assessments in the same imaging session.
l:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.
m:
CSF will be collected by LP after fasting (preferred), or at least 2 hours after the most recent meal.  A gravity drip 
collection method must be used.  Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  The timing of the Baseline LP needs to be scheduled carefully such that subsequent LPs (Visit 7 and 
Visit 18) can be performed at a similar time of day (±1 hour) for each individual subject. The LP must be performed 
after the cognitive tests have been performed; the subject should rest and drink some fluid to hydrate after the 
cognitive tests and before the LP.  The CSF sample will be used for PK and PD assessments.  A CSF sample will also 
Page 1461 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 87 of 144
be stored for testing in the event that the subject develops treatment-emergent adverse events that warrant further 
investigation (eg, treatment-emergent infection).
n:
The PK blood sample should be collected shortly after completing the LP.  The sample should be collected at fasting 
or at least 2 hours after the most recent meal.
o:
The PD and exploratory biomarker blood sample should be collected shortly after completing the LP.  The sample 
should be collected at fasting or at least 2 hours after the most recent meal.
p:
A blood sample will be collected at Baseline and stored.  This sample may be used for exploratory biomarkers 
associated with study drug or disease, or in the event that the subject develops treatment-emergent adverse events that 
warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether 
the subject already had prior exposure to any suspected infective agents.
q:
Viral characterization will include testing for previous exposure to CMV, HSV1, HSV2, etc.
r:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These 
assessments will specifically include evaluation of any areas of depigmentation or any rash.  See Section 9.5.1.5.8 for 
further details.
s:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurological examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.
t:
An ophthalmic examination will be conducted at Visit 2 unless the subject has had a comprehensive eye exam within 
the past 12 months, from which a report is available.  The ophthalmic examination should include fundoscopy to look 
at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields.
Page 1462 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 88 of 144
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Weight
X
X
X
X
X
X
X
X
X
Centralized dermatological assessment via 
photographyg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Ophthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xe
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Blood samples for lymphocyte subset
analysesl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Blood samples for Igsm
X
X
X
X
X
X
X
X
Xe
X
Blood samples for isolation of PBMCs 
X
X
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample for storage for immune statuso
X
X
X
X
X
X
X
X
X
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
Page 1463 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 89 of 144
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
UNS 
Visitd
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EDb
19c
20c
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xy
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood samples for PKt
X
X
X
X
X
X
X
X
Blood samples for PD and exploratory 
biomarkersu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 1464 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 90 of 144
Notes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging,  PBMC = peripheral blood mononuclear cell, PD = pharmacodynamics, PET = positron emission 
tomography, PK = pharmacokinetics, UNS = unscheduled.
a:
Visit 3 should be conducted 7 to 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless additional 
time is required to take Exclusion Criterion #19 into account.  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A window of ±10 days will be permitted for 
Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit windows, every effort should be made to bring 
the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20, respectively).  Subjects who discontinue study drug prematurely will also be 
scheduled to return to the study site for each scheduled visit when clinical efficacy assessments are to be conducted (ie. at Visits 11, 14, 15, 16, 17, and 18, if these visits have 
not already been performed).  At these visits, only clinical efficacy assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB, and ISLT) will be conducted.   Regularly scheduled 
clinical efficacy visits do not need to be attended if they fall within 8 days (visit window) after the Early Discontinuation Visit or within ± 8 days of either of the Follow-Up 
Visits (Visit 19 and Visit 20).  Subjects who discontinue early from study drug are considered on study as long as they return for their regularly scheduled clinical efficacy 
visits as outlined above.
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 2 posttreatment Follow-Up visits; 
one 4 weeks after the last dose of study drug and a second 12 weeks after the last dose of study drug (Visit 19 and Visit 20 respectively).  If clinically indicated, more frequent 
safety assessments can be made as UNS assessments or visits during the posttreatment Follow-Up period.  
d:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
e:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  However, lymphocyte subsets and Igs should 
be repeated at Visit 20 if they were outside of the normal range (regardless of clinical significance) at Visit 19.
f:
Measurements of body temperature and sitting blood pressure and heart rate will be obtained.  
g:
Centralized skin assessments using standardized photography will be conducted by a reviewing dermatologist.  These assessments will specifically include evaluation of any 
areas of depigmentation or any rash.  Additional UNS dermatological assessments should be conducted in response to any dermatological AEs of concern, eg, 
depigmentation, rash, herpetic lesion.
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination, which should 
include fundoscopy to look at the optic disc, macula and the rest of the retina as well as an assessment of visual acuity and visual fields
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
Page 1465 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 91 of 144
l:
Lymphocyte subsets to be measured include CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]) and total 
lymphocytes.  Regulatory T cells will also be measured (CD4, CD25 and CD127, FoxP3). Viability staining may also be employed.
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
o:
Blood samples will be collected and stored.  These samples may be used for exploratory biomarker analyses, or in the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure 
to any suspected infective agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be:  MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors. 
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
addition to sequences for resting state functional MRI.  MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled 
visits.  MRI imaging should be conducted within the 7 days before Visits 14, 16, and 18 and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the 
sponsor will determine whether or not a safety MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.  A volumetric MRI sequence will be collected in all subjects immediately following all safety MRI assessments.
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two plasma PK samples will be obtained:  one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14 and Visit 16 and 4 to 8 hours postdose at 
Visit 7 and Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is 
performed.  Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be 
collected shortly after completing the LP.  If at an ED Visit, the subject has already stopped study drug, then no dosing will take place, but the trough PK sample will still be 
collected, followed by LP at approximately the same time as at previous visits, and then another PK sample shortly after the LP. 
u:
PD and exploratory biomarker blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at 
the same time of day.  At Visits 5, 11, 14, and 16 the PD blood samples should be collected predose.  
v:
All visits at which CSF samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. A CSF 
sample will be collected by LP between 4 and 8 hours postdose and at the same time of day as the subject's Baseline LP (±1 hour).  The CSF sample will be taken with the 
subject fasting (preferred) or at least 2 hours after the most recent meal.  A gravity drip collection method must be used.  The LP will be performed after the cognitive tests; the 
subject should rest and drink some fluid to hydrate after the cognitive tests and before the LP.  Subjects will be encouraged to stay at the site after completion of LP for 
medical observation.  The CSF sample will not be taken at the ED Visit if this visit occurs within 3 months of a previous CSF sample. If at an ED Visit, the subject has already 
stopped study drug, then no dosing will take place, but the CSF sample will still be collected unless it was already collected within the past 3 months. 
w:
Subjects reporting adverse events relating to abnormal dreams, nightmares, or sleep terror will be questioned on the frequency and impact of these events.
Page 1466 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 92 of 144
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time for post-dose 
medical observation.
Page 1467 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 93 of 144
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.1.1.1, and Figure 2.
See Section 9.5.1 for a full description of the procedures and assessments to be performed 
during this study.
Table 8
presents the number of blood and CSF samples, and the total volume of blood 
and CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Number of time points x volume per 
collection 
(mL whole blood or CSF)
Total volume 
(mL whole 
blood or CSF)
Screening and 
Baseline 
Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
18
2 x 5 mL
16 x 5 mL
90 mL
Lymphocyte subset analyses
18
2 x 4 mL
16 x 4 mL
72 mL
PBMC
4
1 x 16 mL
3 x 16 mL
64 mL
IgA, IgM, IgG
9
2 x 2 mL
7 x 2 mL
18 mL
PT, PTT for INR
2
2 x 3 mL
None
6 mL
Thyroid function tests (thyroid 
stimulating hormone, free 
triidothyronine and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis B and C)
1
1 x 4 mL
None
4 mL
Viral characterization
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma 
release assays) 
1
1 x 3 mL
None
3 mL
Sample for immune status
8
1 x 4 mL
7 x 4 mL
32 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 3 mL
6 x 6 mL
39 mL
Pharmacogenetic sample
1
1 x 3 mL
None
3 mL
All blood samples, total volume whole blood collected
  80 mL
322  mL
402  mL
CSF
PD and PK samples
3
1 x 12 mL
2 x 12 mL
36 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, INR = International Normalized Ratio, PBMC = peripheral blood 
mononuclear cell, PD = pharmacodynamics, PK = pharmacokinetic, PT = prothrombin time, PTT = partial thromboplastin 
time.
Page 1468 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 94 of 144
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
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 
when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study drug, ie, through to the second follow-up visit (Visit 20).  In subjects who 
discontinue study drug early, but continue with efficacy assessments, SAEs only need to be 
solicited up to 3 months after the last dose of study drug. However, any SAEs volunteered 
by subjects after this time point must be reported according to standard procedures.  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.
Page 1469 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 95 of 144
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Page 1470 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 96 of 144
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should always be considered serious
important medical events and be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the 
study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
Page 1471 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 97 of 144
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue study drug or withdraw from the study at any time for any 
reason.  All subjects who discontinue taking study drug prematurely for any reason will 
undergo an ED Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  In 
addition, Follow-Up Visits will be scheduled 4 and 12 weeks after the last dose of study drug 
(Visit 19 and Visit 20, respectively) (see Section 9.1.2.3).  See Table 7 for full details of the 
assessments to be performed at these visits.  Subjects who discontinue study drug 
prematurely will also be scheduled to return to the study site for each scheduled visit when 
clinical efficacy assessments are to be conducted (ie, at Visits 11, 14, 15, 16, 17, and 18, if 
these visits have not already been performed).  At these visits, only clinical efficacy 
assessments (MMSE, CDR, ADAS-cog14, FAQ, CBB and ISLT) will be conducted.  
Subjects who discontinue early from study drug are considered on study as long as they 
return for their regularly scheduled clinical efficacy visits as outlined above. Subjects who 
discontinue study drug early (as opposed to subjects whose dosing with study drug is 
temporarily suspended under Medical Monitor guidance) will not be permitted to restart 
study drug.
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will 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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, 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 withdrawal from the 
study.  Study disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
Page 1472 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 98 of 144
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
Page 1473 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 99 of 144
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal 
subjects as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

The derived ADCOMS at 18 months of treatment in mild AD subjects
9.7.1.1.3
EXPLORATORY ENDPOINTS
Change from baseline in:  
Page 1474 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 100 of 144

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild AD 
subjects

Total hippocampal volume at 12 and 18 months of treatment in mild AD subjects as 
measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild AD 
subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 
18 months of treatment, and during posttreatment follow-up in MCI/Prodromal and 
mild AD subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 and, 
18 months in MCI/Prodromal and mild AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal 
and mild AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild AD subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who 
sufficiently comply with the protocol.  The PP Analysis Set will be used to conduct a 
sensitivity analysis of the primary efficacy endpoint.  Details of the evaluability 
criteria will be determined before database lock and treatment unblinding, and will be 
specified in the statistical analysis plan.

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 
plasma concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement 
and at least 1 posttreatment PD measurement.
Page 1475 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 101 of 144
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical subpopulation 
(MCI/Prodromal AD or mild AD).  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
WHO DD preferred term.  Prior medications will be defined as medications that stopped 
Page 1476 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 102 of 144
before the first dose of study drug.  Concomitant medications will be defined as medications 
that (1) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (2) started on or after the date of the first dose of study drug up to the
date of the last dose.  All medications will be presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
9.7.1.6
Efficacy Analyses
MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment 
effect.  

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success 
criteria if the probability that the ED90 at 18 months of treatment achieves 25% 
improvement over placebo is at least 80%.  Early success is achieved before all 
MCI/Prodromal subjects complete 18 months of treatment and can only be 
determined after at least 200 MCI/Prodromal subjects have been randomized.  If early 
success is declared before full randomization, the randomization of new 
MCI/Prodromal subjects will stop but subjects already randomized into the study will 
receive the full 18 months of treatment (following confirmation from the Sponsor’s 
Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria 
if the probability that the ED90 is better than placebo by the clinically significant 
difference of 25% is less than 5% at 18 months of treatment.  The statistical futility 
boundary is binding; if the statistical futility boundary is crossed the study will be 
considered to have failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success 
if an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild AD Cohort
The analysis of the Mild AD cohort is based on the group sequential design.  Interim 
analyses in the Mild AD cohort will only be performed after the MCI/Prodromal cohort 
Page 1477 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 103 of 144
crosses the early success boundary.  The early efficacy signal based on the change from 
baseline of ADCOMS at 18 months is defined as crossing the interim-analysis boundaries for 
overwhelming efficacy in the mild AD population.  The O’Brien-Fleming (OF) boundaries 
based on Lan-DeMets alpha spending function will be used to assess overwhelming efficacy.  
The corresponding OF boundaries based on P values will be 0.076, 0.0221, and 0.0423 for 
the first, second, and final analyses, respectively, according to 2 planned interim analyses at 
the 60% and 80% information fraction.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of primary endpoint
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
Sensitivity analysis of primary endpoint
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have 
been lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
Page 1478 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 104 of 144
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  Other covariates such as adjusted 
hippocampal volume will be studied.  These analyses will be performed as sensitivity 
analyses on the FAS as well as the PP set and as such, no multiplicity adjustments will be 
made to account for the interim analyses.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment 
in MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild AD Cohort
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild AD.  If there is no treatment group-by-population interaction in the overall 
study, the MMRM analysis will include all subjects (MCI/Prodromal or mild AD) in the 
overall study.  Otherwise, the MMRM analysis will only include subjects in the mild AD 
cohort.  The comparison between placebo and active doses will be performed within mild 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will 
be used to control for multiplicity due to multiple comparisons.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and 
mild AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild AD 
subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 
months in mild AD subjects.  Data from early discontinuations will also be included. 
Page 1479 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 105 of 144

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in 
MCI/Prodromal and mild AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements 
after 4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild 
AD subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 
months in MCI/Prodromal and mild AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 
and 18 months in MCI/Prodromal and mild AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual E2609 concentration listings.  The PK 
Analysis Set will be used for summaries of E2609 concentrations. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Page 1480 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 106 of 144
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in CSF will 
be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  The PK/PD relationship between plasma PK parameters with other 
biomarkers may also be explored using similar methods.
Additionally, the relationship between plasma and CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between plasma and CSF exposure to E2609 
and the change from baseline for 18 months in the ADAS-cog, the CDR, and the MMSE,
will be explored graphically.  Any emergent relationship will be explored through population 
PK/PD modeling.
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Page 1481 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 107 of 144
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the 
AE is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and preferred term.  A subject will be counted only once within an SOC and preferred 
term, even if the subject experienced more than 1 TEAE within a specific SOC and preferred 
term.  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 preferred term.  Treatment-related TEAEs include those events considered by the 
investigator to be related to study drug.  The number (percentage) of subjects with treatment-
related TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical subpopulation 
(MCI/Prodromal or mild AD).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and preferred term for each treatment group.  A subject data listing of all AEs 
leading to death will be provided.
Page 1482 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 108 of 144
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and preferred term for each treatment group.  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 preferred term for each treatment group.  A 
subject data listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
Page 1483 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 109 of 144
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 msec

QTc interval >480 msec

QTc interval >500 msec
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 msec

QTc interval increases from baseline >60 msec
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE, CDR, and CBB (see 
Section 9.7.1.6).
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
Page 1484 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 110 of 144
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 0.15 
(SUVR), respectively; this would require a total of 100 subjects from all 4 arms at 18 months 
to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild AD Cohort
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the mild AD cohort in Section 9.7.1.6.2.  The statistical 
power was estimated through simulation for the dose-response assumption that the percent 
reduction in change from baseline of ADCOMS at 18 months compared with placebo would 
be 33% and 50% corresponding to the 2 doses, respectively.  The estimated power for the 
actual planned 200 mild AD subjects is at least 80% assuming a 2-sided alpha of 0.05.
Page 1485 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 111 of 144
9.7.3
Interim Analysis
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of 
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
An interim analysis will be conducted for safety when the first 60 MCI/Prodromal subjects 
have completed 12 weeks of treatment (or discontinue study drug early).  
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, 60 subjects from Stage A of the study and 
the first 40 subjects from Stage B of the study).  Further interim efficacy analyses will be 
conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 
Page 1486 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 112 of 144
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
The Mild AD Cohort
A group sequential design will be used for the mild AD cohort.  This design includes 3 looks, 
2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
The information fraction is the number of assessments in all treatment arms divided by the 
total number of expected assessments.  Interim analyses will be performed after the 
MCI/Prodromal cohort crosses the early success boundary.  The corresponding efficacy 
boundaries will be 0.076, 0.022, and 0.0423 for the first, second, and final analyses, 
respectively.  If the actual information fraction during the interim analyses is different from 
60% or 80% at the interim, the efficacy boundaries will be adjusted based on the actual 
information fraction.  
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild AD subjects.  In the event of futility in the MCI/Prodromal cohort, 
an analysis will be performed for the mild AD cohort based on the data for mild AD subjects 
available at that time. 
Randomization into the Mild AD cohort will remain at a fixed schedule throughout Stage B 
of the study.  
The interim analyses in the Mild AD cohort will be conducted by an independent analysis 
group.
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses).  
Randomization probabilities to each treatment group will be updated at each interim analysis, 
such that the randomization probability will be increased for the placebo group and dosage 
groups that represent the potential target dose (ED90), and simultaneously decreased for other 
active arms.  
Page 1487 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 113 of 144
Within the 2 clinical populations (MCI/Prodromal and mild AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or 
memantine or both (yes or no).
Subjects with mild AD will be randomized to placebo or 1 of 2 dose groups of E2609.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 1488 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 114 of 144
10 REFERENCE LIST
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community 
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology 
2007;68:1588-95.
Page 1489 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 115 of 144
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on 
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Page 1490 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 116 of 144
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Page 1491 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 117 of 144
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
25.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 1492 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 118 of 144
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 1493 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 119 of 144
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for 
accuracy after production

Recorded data from automated instruments such as IxRS, x-rays, and other 
imaging reports (eg, sonograms, computed tomography scans, MRIs, radioactive 
images, ECGs, rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 1494 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 120 of 144
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 1495 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 121 of 144
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 CTA 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 CTA 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 CTA executed between the 
institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
Page 1496 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 122 of 144
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
< 0.70 103/uL – 800/mm3
<0.70 – 0.8109/L
(ULN=3.10 103/µL)
<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 
<1.40– 1.5109/L
<1.40 103/uL – 1500/mm3
(ULN=7.00 103/µL)
<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
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
3.6 g/dL – 4.8 g/dL
69 -79 years (LLN-ULN)
3.5g/dL – 4.8g/dL
79 -89 years (LLN-ULN)
3.5g/dL – 4.7g/dL
89 -150 years (LLN-ULN)
3.2g/dL – 4.6g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Male:
>44 – 3.0 x 44
Female:
>3.0 – 5.032
Male
>3.0 – 5.044
Female:
>5.0 – 20.032
Male:
>5.0 – 20.044
Female:
>20.032
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Page 1497 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 123 of 144
Grade 1
Grade 2
Grade 3
Grade 4
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>6.01.00
Male
>1.5 mg/dL-3.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
<2.5 – 2.5 mg/dL
<0.81 – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
>5.5 – 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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 1498 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 124 of 144
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1, Listing 2, Listing 3, Listing 4, Listing 5, and 
Listing 6.  Medications permitted with restrictions are listed in Listing 7, Listing 8, and  
Listing 9.  These may not be all-inclusive listings.  Please contact the medical monitor(s) if 
the investigators have any questions or concerns regarding any medication not listed that 
your subjects may be taking before enrollment or start during the course of the E2609-G000-
202 study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 9 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Page 1499 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 125 of 144
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Randomization until after the last 
treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, 
Torsades de Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Blaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Page 1500 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 126 of 144
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; 
names may be the ® or ™)
Comments
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 1501 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 127 of 144
Listing 2 Prohibited Medications Within 7 Days (or 5 Half-lives, Whichever is Longer) 
Before Randomization and Until after the Last Treatment Visit)
Generic Name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Anticoagulants
Adeporin
Normiflo
Alteplase, tPA
Activase, Cathflo Activase
Anisindione
Miradon
Antithrombin III
ATryn, Thrombate III
Argatroban
Argatroban
Bivalirudin
Angiomax
Dabigatran
Pradaxa
Dalteparin
Fragmin
Danaparoid
Orgaran
Dicumarol
Dicumarol
Enoxaparin
Lovenox
Fondaparinux 
Arixtra
Heparin Sodium
Monoject
Lanoteplase
Lanoplase
Lepirudin
Refludan
Pentosan polysulfate sodium
Elmiron
Reteplase
Retavase, Retevase
Staphylokinase
Eskinase, Heberkinasa Kabikinase, Streptase, Thrombosolv, 
Zykinase
Streptokinase
Streptase
Tenecteplase
TNKase
Tinzaparin
Innohep
Urokinase
Abbokinase, Kinlytic
Warfarin
Coumadin, Jantoven
Antiplatelet drugs
Aspirin and Plavix (only in subjects 
undertaking lumbar puncture in biomarker 
subgroup)
Aspirin or clopidogrel is permitted in all subjects.  Aspirin and 
clopidogrel in combination is permitted in subjects who are not to 
undergo lumbar puncture.
Note:  This list is not exhaustive.
Page 1502 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 128 of 144
Listing 3 Prohibited Medications Within 5 Half Lives or 60 Days, Whichever is 
Longer, Before Randomization and Until after the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Systemic Immunosuppressantsa and Immunomodulatory therapy
Azathioprine
Azasan, Imur
Ciclosporine
Gengraf, Neoral
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Fingolimod
Gilenya
Methotrexate
Trexall
Methylprednisolone
Medrol, Meprolone
Mycophenolate
CellCept, Myfortic
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
Page 1503 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 129 of 144
Listing 4 Prohibited Medications Within 6 Months Before Randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may 
be the ® or ™)
Immunoglobulin therapy
Adalimumab
Humira
Bevacizumab
Avastin
Efalizumab
Raptiva
Etanercept
Enbrel
Immune globulin 
IV, IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Infliximab
Remicade
Omalizumab
Xolair
Ranibizumab
Lucentis 
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 1504 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 130 of 144
Listing 5 Prohibited Live Vaccines Within 3 Months Before Randomization Until after 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
Typhoid vaccination (oral)
Mumps vaccination
Note:  This list is not exhaustive 
Page 1505 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 131 of 144
Listing 6 Strong CYP3A4 Inhibitors Prohibited Within 5 Half-Lives or 14 Days 
(Whichever Is Longer) Before Randomization Until After the Last Treatment Visit
Generic name
Brand name(s)
boceprevir
Victrelis
clarithromycin
Clarithromycin, clarithromycin extended release, Prevpac
cobicistat 
Tybost, Stribild, 
conivaptan
Vaprisol
danoprevir
elvitegravir
Vitekta, Stribild
indinavir
Crixivan
itraconazole
Sporanoz, Onmel
ketoconazole
Xolegel, Nizoral, Ketodan
lopinavir
Kaletra
nefazodone
Serzone
nelfinavir
Viracept
posaconazole
Noxafil
ritonavir
Norvir, Kaletra
saquinavir
Invirase, Fortovase
telaprevir
Incivek
telithromycin
Ketek
tipranavir
Aptivus
troleandomycin
Triocetin
voriconazole
Vfend, Voriconazole
Note:  This list is not exhaustive 
Page 1506 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 132 of 144
Permitted Prior/Concomitant Medications
Listing 7
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Follow-Up Visit 2
Generic name
Brand name (Names shown are not exhaustive and are 
examples only; names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Galantamine
Reminyl
Memantine
Namenda
Rivastigmine
Exelon
Note:  This list is not exhaustive.
Page 1507 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 133 of 144
Listing 8
Permitted Medications Used on PRN Basis Which are Not to be Used 
Within 72 Hours before Cognitive Testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph 
SR, RMS, Roxanol
Opiate Agonists
Codeine
Codeine
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Meperidine
Demerol, Meperitab
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Amitriptyline
(various)
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Dothiepin
(various)
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Lorazepam
Ativan
Midazolam
Versed
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Ramelteon
Rozerem
Risperidone
Risperdal
Temazepam
Restoril
Triazolam
Halcion
Zolpidem
Ambien; others
Zopiclone
(various)
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
Note:  This list is not exhaustive 
PRN = Pro re nata
Page 1508 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 134 of 144
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
If to be used on a PRN basis see Listing 8.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Amitriptyline hydrochloride 
Elavil
Amoxapine
Amoxapine
Bupropion
Aplenzin, Budeprion, Buproban, 
Zyban, Wellbutrin
Citalopram
Celexa
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Desvenlafaxine
Pristiq
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Duloxetine
Cymbalta
Escitalopram
Lexapro
Fluoxetine
Prozac, Sarafem, Selfemra
Fluvoxamine
Luvox 
Imipramine hydrochloride 
Tofranil
Isocarboxazid
Marplan
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Nortriptyline hydrochloride 
Aventyl, Pamelor
Paroxetine
Paxil, Pexeva
Phenelzine
Nardil
Protriptyline hydrochloride 
Vivactil
Rasagiline
Azilect
Selegiline
EMSAM
Sertraline 
Sertaraline, Zoloft
Tranylcypromine
Parnate
Trazodone hydrochloride 
Desyrel, Oleptro
Trimipramine maleate 
Surmontil
Venlafaxine hydrochloride
Effexor
Page 1509 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 135 of 144
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, 
Tegretol XR 
Lamotrigine
Lamictal, Lamictal CD, Lamictal 
ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, 
Depakote ER, Divalproex Sodium, 
Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone
Risperdal
Thioridazine
Mellaril
Thiothixene
Navane
Trifluoperazine
Stelazine
Benzodiazepines
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Chlordiazepoxide
H-Tran, Librium
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Estazolam
ProSom
Flunitrazepam
Rohypnol
Flurazepam
Dalmane
Page 1510 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 136 of 144
Listing 9
Permitted Centrally Active or Psychiatric Medications
Generic Name
Brand name (Names shown are not exhaustive 
and are examples only; names may be the ® or 
™)
Lorazepam
Ativan 
Midazolam
Versed
Temazepam
Restoril
Triazolam
Halcion
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, 
Stilnox, Stilnoct, Sublinox, Hypnogen, 
Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 1511 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 137 of 144
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
Page 1512 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 138 of 144
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
Page 1513 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 139 of 144
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 1514 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 140 of 144
Appendix 4
AEs Indicating Signals of Possible Drug Abuse 
Potential
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
1
Euphoric mood
Euphoric mood
Euphoria
Euphoric
Exaggerated well-being
Excitement excessive
Feeling high
Felt high
High
High feeling
Laughter
2
Elevated mood
Elevated mood
Mood elevated
Elation
3
Feeling abnormal
Feeling abnormal
Cotton wool in head
Feeling dazed
Feeling floating
Feeling strange
Feeling weightless
Felt like a zombie
Floating feeling
Foggy feeling in head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Spaced out
Unstable feeling
Weird feeling
Spacey
4
Feeling drunk
Feeling drunk
Drunkenness feeling of
Drunk-like effect
Intoxicated
Stoned
Drugged
5
Feeling of relaxation
Feeling of relaxation
Feeling relaxed
Relaxation
Relaxed
Increased well-being
Page 1515 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 141 of 144
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Excessive happiness
6
Thinking abnormal
Thinking abnormal
Abnormal thinking
Thinking irrational
Thinking disturbance
Thought blocking
Wandering thoughts
7
Hallucination
Hallucination
Illusions
Flashbacks
Floating
Rush
Feeling addicted
8
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Feeling happy inappropriately
Inappropriate affect
Inappropriate elation
Inappropriate laughter
Inappropriate mood elevation
9
Mood disorders and 
disturbances
Mental disturbance
Depersonalisation
Psychomotor stimulation
Mood disorders
Emotional and mood disturbances
Delirium
Delirious
Mood altered
Mood alterations
Mood instability
Mood swings
Emotional lability 
Emotional disorder
Emotional distress
Personality disorder
Impatience
Abnormal behavior
Delusional disorder
Irritability
10
Drug tolerance
Drug tolerance
Habituation
Drug withdrawal syndrome
Substance-related disorders
11
Psychosis
Psychosis
Page 1516 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 142 of 144
Category
Examples of AEs Indicating Signals of Possible Drug 
Abuse Potential
Psychotic episode or disorder
12
Dissociative State
Dissociation
Disconnected
Derealisation
Depersonalisation
Detached
Sensation of distance from one's environment
Loss of a sense of personal identity
Page 1517 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 143 of 144
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, 
Proof-of-Concept, 
Dose-Finding 
Study 
To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild Dementia Due to 
Alzheimer’s Disease
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product 
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 1518 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL:V2.0, 21 Oct 2014
Confidential
Page 144 of 144
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof-of-Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild Dementia Due to 
Alzheimer’s Disease
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 1519 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 1 of 139
1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2609-G000-202
Study Protocol 
Title:
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, 
Proof
of Concept, Dose-Finding Study To Evaluate Safety, 
Tolerability and Efficacy of E2609 in Subjects With Mild Cognitive 
Impairment due to Alzheimer’s Disease (Prodromal Alzheimer’s 
Disease) and Mild Dementia Due to Alzheimer’s Disease
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Eisai Ltd.  
European Knowledge 
Centre
Mosquito Way
Hatfield, 
Hertfordshire 
AL10 9SN 
United Kingdom
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2609
Indication:
Alzheimer’s disease
Phase:
2
Approval Date:
V1.0
15 July 2014 (original protocol)
IND Number:
109308
EudraCT Number:
2014-002723-94
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All 
required study documentation will be archived as required by 
regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
Page 1520 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 2 of 139
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:
E2609
Name of Active Ingredient:
N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-
4-fluorophenyl}-5-(difluoromethyl)pyrazine-2-carboxamide
Study Protocol Title
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof of Concept, 
Dose-Finding Study To Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects With 
Mild Cognitive Impairment due to Alzheimer’s Disease (Prodromal Alzheimer’s Disease) 
and Mild Dementia Due to Alzheimer’s Disease
Investigators
Stage A:  Investigators in United States only
Stage B:  Multinational investigators
Sites
Stage A:  Approximately 25 sites, United States only
Stage B:  Approximately 125 sites, globally
Study Period and Phase of Development
Stage A:  Approximately 32 months and will continue and overlap with Stage B
Stage B:  A maximum of 40 months from initiation of Stage B
Phase 2
Objectives
Primary Objectives
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with Mild Cognitive Impairment due to Alzheimer’s 
Disease/ Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal throughout the 
protocol)
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
Mild Dementia due to Alzheimer's Disease (referred to as mild AD throughout the 
protocol)
Page 1521 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 3 of 139
Secondary Objectives
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI)
2. To evaluate the effect of E2609 compared with placebo on amyloid β(1-x) (Aβ[1-x]) in 
cerebrospinal fluid (CSF) after 4 weeks and 18 months of treatment in MCI/Prodromal 
subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at
18 months in mild AD subjects
Exploratory Objectives
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in 
CSF after 4 weeks and 18 months of treatment in mild AD subjects
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during post treatment follow-up, in 
MCI/Prodromal and mild AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b.
The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d.
The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF β-amyloid converting enzyme 1 (BACE1)
measurements during 18 months of treatment and during post treatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume and total ventricular volume at 6, 12, and 18 months of treatment and during 
post treatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
Page 1522 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 4 of 139
7. To characterize the population pharmacokinetics (PK) of E2609 in MCI/Prodromal and 
mild AD subjects, and to examine the effect of intrinsic and extrinsic factors (including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild AD subjects
Study Design
This will be a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild AD.  A common set of 
inclusion criteria, consistent with the National Institute on Aging – Alzheimer’s Association 
(NIA-AA) clinical research criteria for Mild Cognitive Impairment (MCI) due to 
Alzheimer’s Disease (AD) or mild AD, will be required for all subjects.  In addition the MCI 
due to AD population will also qualify under the research criterion for “Prodromal AD.”  As 
the non-demented subjects will fulfill the criteria for both MCI due to AD and Prodromal AD 
they will be identified as MCI/Prodromal subjects in this protocol. 
The diagnosis of 
MCI/Prodromal AD or mild AD will be based on both clinical and biological (ie, 
confirmation of amyloid load in the brain) criteria.  
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) in MCI/Prodromal subjects before expanding enrollment to include a larger 
population of MCI/Prodromal subjects in Stage B.  In addition, during Stage B of the study, 
subjects with mild AD will be randomized to form a separate mild AD cohort.  All 
MCI/Prodromal subjects will be included in the primary efficacy evaluation irrespective of 
whether they were recruited during Stage A or Stage B of the study.  Bayesian adaptive 
randomization will be used in the MCI/Prodromal cohort only during Stage B.  
Both Stage A and Stage B of the study will consist of 2 phases: Prerandomization and 
Randomization.  The Prerandomization Phase (up to 60 days) includes a Screening Visit
(Visit 1) and a Baseline Visit (Visit 2).  All screening assessments (within 4 distinct tiers)
must be completed, and eligibility to continue in the study confirmed, before any baseline 
assessments commence.  Following successful completion of the Prerandomization Phase, 
eligible subjects will be randomized and will enter the Randomization Phase, which will 
consist of 2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
Stage A
Stage A will enroll 60 eligible MCI/Prodromal AD subjects who will be randomized (at 
Visit 3) 1:1:1:1 to 4 treatment groups.  In addition to the placebo group, 3 E2609 doses will 
be used to reduce CSF amyloid β levels by approximately 25% (5 mg), 50% (15 mg), and 
75% (50 mg) from baseline, respectively, at steady state.  PK/pharmacodynamic (PD) 
modeling has shown that these doses should achieve these targets when administered once 
daily (QD) with food, and these doses will be confirmed or adjusted based on the 4-week 
assessment of CSF Aβ(1-x)
Page 1523 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 5 of 139
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A of the study, an independent data safety monitoring board (DSMB; including at least 
1 immunologist) will review all safety data in an unblinded manner.  The DSMB will make 
recommendations to Eisai after each review as to whether any change(s) to the study are 
necessary.  Unless the DSMB recommends otherwise, randomization of subjects into 
Stage A of the study will continue until 60 MCI/Prodromal subjects have been randomized
and dosed.  
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B.  If the 95% confidence interval of the mean percentage change from 
baseline in CSF Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 does not 
include its intended target value (ie, 25%, 50% and 75% reductions from baseline,
respectively for E2609 at 5 mg, 15 mg, and 50 mg QD), PK/PD modeling will be conducted.  
From this model, the new target plasma steady state concentrations of E2609 required to 
achieve the target levels of CSF Aβ(1-x) reduction will be estimated again.  Dose adjustment 
for Stage B may be considered if it is possible to get closer to the new target plasma steady 
state concentrations of E2609 required to achieve the intended target levels of CSF Aβ(1-x) 
reduction than is possible with the initially planned doses, given the limitation that E2609 
dose adjustments will have to be in 5-mg increments or decrements.  Subjects already 
randomized to a dose that needs to be adjusted will be switched to the new adjusted dose and 
complete their treatment at this new dose.
Once 60 MCI/Prodromal subjects in Stage A have completed at least 12 weeks of treatment, 
an interim safety analysis will be conducted by Eisai and the DSMB.  Subjects in Stage A 
will continue study drug while the DSMB reviews all the available safety data, but
randomization of additional subjects will not take place (ie, recruitment into Stage B will not 
commence) until the safety analysis is completed by the DSMB.  
Stage B
Stage B will start after the DSMB safety review of Stage A has shown acceptable safety and 
tolerability of E2609 and after the doses of E2609 to be used in Stage B are confirmed.  
Stage B will enroll, randomize, and dose up to an additional 440 eligible MCI/Prodromal 
subjects.  In addition, a separate cohort of approximately 200 mild AD subjects will be 
randomized and dosed during Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment to the study is 
completed; following this the DSMB will meet approximately every 6 months.  
Both population cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD) whereas the mild AD cohort 
will only include 2 doses of E2609 (15 mg and 50 mg QD).  
Bayesian adaptive randomization will be used in the MCI/Prodromal cohort only during 
Stage B.  The first 40 MCI/Prodromal subjects recruited into Stage B will be randomized 
according to a fixed schedule (1:1:1:1; placebo: 5 mg E2609: 15 mg E2609: 50 mg E2609) 
Page 1524 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 6 of 139
and the remaining subjects in the MCI/Prodromal cohort in Stage B will be randomized 
according to response adaptive randomizations based on the ADCOMS results using the 
Bayesian interim efficacy analyses.  The mild AD subjects will be randomized according to a
fixed schedule (1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B of the study.
Early discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who 
discontinue study drug prematurely will also be scheduled to return to the study site to 
undertake limited efficacy assessments (MMSE, CDR, ADAS-cog14, CBB, and ISLT) at 
Week 53 (Visit 16) and Week 79 (Visit 18), if these 2 visits have not already been 
performed.
Follow up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
Number of Subjects

Stage A:  Approximately 250 MCI/Prodromal subjects will be screened to provide 
60 randomized subjects (target of 15 subjects per treatment arm).  

Stage B:  Approximately 1850 MCI/Prodromal subjects will be screened to provide up to 
440 enrolled subjects.  The final number of MCI/Prodromal subjects will depend upon 
whether the prespecified criteria for either early success or futility are met.  In addition, 
approximately 835 subjects with mild AD will be screened to provide approximately 
200 randomized mild AD subjects.
Inclusion Criteria
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD or AD 
dementia and is "staged" or classified as either MCI (Stage A and Stage B) or mild 
dementia (Stage B only) and also complies with the following:  
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤20
d.
MMSE ≥20
2. Amyloid positive PET image based on centralized PET scan reading 
3. Males and females aged 50 to 85 years, inclusive at time of consent
Page 1525 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 7 of 139
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. Subjects who are receiving acetylcholinesterase inhibitors (AChEIs) or memantine must 
be on a stable dose for at least 12 weeks before the baseline cognitive assessments at 
Visit 2, with no plans for dose adjustment in the foreseeable future.  Treatment-naïve 
subjects can be entered into the study but there should be no plans to initiate treatment 
with AChEIs or memantine at the time of entry into the study.
6. Subjects must have been on stable doses of all other permitted chronically used 
concomitant medications (ie, not related to their cognitive decline) for at least 4 weeks 
before randomization.
7. Females must not be lactating or pregnant (as documented by a negative beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
8. Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days before study entry and must agree to use a highly effective method of 
contraception other than hormonal contraceptives (eg, total abstinence, an intrauterine 
device, a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) throughout the entire study period and for 30 days after study 
drug discontinuation.  If currently abstinent, the subject must agree to use a double 
barrier method as described above if she becomes sexually active during the study period 
or for 30 days after study drug discontinuation.  Females who are using hormonal 
contraceptives must have been on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and must continue to use the same 
contraceptive during the study and for 30 days after study drug discontinuation.  All 
females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for ≥12 consecutive months, in the appropriate age group and without other 
known or suspected cause) or have been sterilized surgically (ie bilateral tubal ligation, 
total hysterectomy or bilateral oophorectomy, all with surgery ≥1 month before dosing).
Page 1526 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 8 of 139
9. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they 
and their female partners must meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 30 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 30 days after study drug discontinuation.
10. Provide written informed consent
11. Willing and able to comply with all aspects of the protocol
Exclusion Criteria
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or magnetic resonance imaging (MRI)
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (eg, arachnoid cysts) or brain tumors (eg, meningioma).
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild AD diagnosis or could 
interfere with study assessments or procedures 
7. A score of ≥8 on the 15-item Geriatric Depression Scale at Screening
8. Abnormally low serum vitamin B12 levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the lower limit of normal (LLN) for 
the testing laboratory).
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
11. Any contraindications to lumbar puncture for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
Page 1527 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 9 of 139
12. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
13. History of immunoglobulin (Ig) deficiency or other immunodeficiency disorders 
(including subjects known to be human immunodeficiency virus positive)
14. Subjects with chronic viral hepatitis
15. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
16. A history of ophthalmic shingles
17. A history of ocular herpes simplex virus (HSV) infection
18. Any live vaccine in the 3 months before randomization 
19. Any active infection within the last 4 weeks before randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR, etc) must be repeated.
20. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
21. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
22. Ig (IgG, IgA, or IgM) levels below the LLN
23. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
24. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate electrocardiograms 
(ECGs).  A history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, 
family history of long QT Syndrome) or the use of concomitant medications that prolong 
the QT/QTc interval.  
25. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
26. Left bundle branch block at Screening or Baseline 
27. Persistent heart rate <50 or >100 beats per minute at Screening or Baseline
28. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
Page 1528 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 10 of 139
29. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
30. Type 1 or Type 2 diabetes mellitus that is not well controlled
31. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
32. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
33. Hypopigmentation conditions (eg, albinism and vitiligo)
34. Known or suspected history of drug or alcohol dependency or abuse within 2 years 
before Screening, current use of recreational drugs or a positive urine drug test at 
Screening.  Subjects who test positive for benzodiazepines or opioids in the urine drug 
screen need not be excluded if in the clinical opinion of the investigator, this is due to the 
subject taking prior/concomitant medications containing benzodiazepines or opioids for a 
medical condition that is not exclusionary and not due to drug abuse.
35. Has a “yes” answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal 
ideation questions 4 or 5, or any suicidal behavior assessment within 6 months before 
Screening, at Screening, or at the Baseline Visit; or has been hospitalized or treated for 
suicidal behavior in the past 5 years before Screening
36. Violations of the medical restrictions as specified in the Concomitant Medications 
section of the protocol
37. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can 
be undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
38. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
39. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
40. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors,
or to the PET tracer, or components of its formulation
Page 1529 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 11 of 139
Study Treatments
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets to 
match E2609 will be of identical appearance.  Each subject will receive 2 tablets, which
when combined will make up the required doses of E2609 (see below) or placebo, to be 
administered orally QD with food.  

MCI/Prodromal Cohort:  3 doses (5 mg, 15 mg, and 50 mg) of E2609 or placebo

Mild AD Cohort:  2 doses (15 mg and 50 mg) of E2609 or placebo.  
Duration of Treatment
The maximum duration of a subject’s participation in the study will be approximately 
2 years, comprising: 

Screening and Baseline Periods (Prerandomization Phase):  up to 60 days
-
In subjects who have an active infection within 4 weeks of the planned randomization 
date, the duration of the pre-randomization phase can be extended by up to 4 weeks 
to allow additional time for resolution of the infection.

Treatment Period (Randomization Phase): up to 78 weeks

Follow-Up Period (Randomization Phase):  12 weeks (post last dose)
Concomitant Drug/Therapy
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives or 
7 days (whichever is longer) before randomization

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted 
for a period of 5 half-lives or 60 days (whichever is longer) before randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
Page 1530 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 12 of 139
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.  
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if, in the 
opinion of the investigator, this will not interfere with study procedures or subject safety, and 
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
Assessments
Efficacy Assessments
Derived ADCOMS:  The derived ADCOMS represents a new approach to the analysis of 
selected items (12 total) from 3 fully validated and well established clinical tools, the 
ADAS-cog (4 items), the MMSE (2 items), and the CDR (all 6 items).  The 3 scales should 
be administered in full in the morning, or, if not possible, consistently at the same time of 
day.
Alzheimer's Disease Assessment Scale - cognitive subscale:  The 14-item version will be 
used since it is considered more relevant for subjects with MCI/Prodromal AD or mild AD.
Mini Mental State Examination:  A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  
Clinical Dementia Rating:  Assesses 6 domains of subject function; memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal care.  
CogState Brief Battery: A computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test.  Speed of response is the measure.
2. Identification – a simple choice reaction time test.  Speed of response is the measure.
3. One Card Back – a simple working memory test.  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test.  Accuracy of response is the 
measure.
Page 1531 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 13 of 139
International Shopping List Task: The ISLT is a verbal learning and memory test assessing 
both immediate and delayed recall.  
Functional Assessment Questionnaire: The FAQ has 10 items concerned with performing 
daily tasks necessary for independent living.  Either a caregiver or informant or the subject 
provides performance ratings on 10 complex activities of daily living performed within the 
preceding 4 weeks.  
Volumetric Magnetic Resonance Imaging: 
vMRI will be used to evaluate disease 
modification, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.
Pharmacokinetic Assessments
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed depending on emerging 
data from other studies with E2609.
Pharmacodynamic, Pharmacogenomic and Other Biomarker Assessments
Brain atrophy will be measured by vMRI: see Efficacy Assessments (above).  
The soluble biomarkers Aβ(1-x), Aβ(1-42), total tau (t-tau), and p-tau will be measured in 
CSF.  BACE1 levels and activity in CSF will also be measured.  
Amyloid PET imaging will be used to confirm that all subjects eligible for progression to the 
Baseline Period of the study have amyloid deposition in the brain.  Longitudinal amyloid 
PET imaging will also be conducted after 18 months of treatment (or at ED, providing the 
subject has received at least 39 weeks of study drug).  Longitudinal amyloid PET imaging 
will only be conducted through to the time at which acceptable 18-month PET scans have 
been obtained for at least 25 subjects per treatment arm for each amyloid PET ligand used.
Apolipoprotein E (ApoE) and NAT2 genotyping/phenotyping will be conducted.  ApoE4
homozygous or heterozygous status and NAT2 status will be used in the statistical analysis to 
determine the effects on treatment response and safety.  Remaining genomic DNA may also 
be stored for up to 15 years to be used to examine the role of DNA sequence variability on 
the absorption, distribution, metabolism, and elimination of E2609, development of adverse 
events (AEs), as well as the underlying AD.  Variations in E2609 exposure or the occurrence 
of AEs observed in the study population may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety, or PD data.  
Safety Assessments
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments.  Routine safety assessments will include the monitoring and recording all AEs 
and serious AEs, monitoring of hematology, blood chemistry, and urinalysis, measurement 
of vital signs, regular ECGs, physical and neurological examinations, and dermatological 
Page 1532 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 14 of 139
assessments at regular intervals.  Information for AEs relating to abuse potential will be 
collected via a detailed narrative.  Subjects reporting AEs relating to abnormal dreams or 
sleep-related events, or sleep terror will be questioned on the frequency and impact of these 
events.
Complete blood counts and lymphocyte subset absolute counts and percentages will be 
measured (by a centralized laboratory) every week for the first month, every 2 weeks for the 
next 2 months (Months 2 and 3) and monthly for the next 3 months (Months 4, 5, and 6).  
Thereafter they will be monitored every 3 months until the end of the Treatment Period and 
at both Follow-Up Visits.  Serum IgG, IgA, and IgM will be monitored monthly for the first 
3 months, at 6, 12, and 18 months, and at both Follow-Up Visits.  
Assessments by a dermatologist will be performed at baseline and at 3-month intervals 
during the Treatment Phase of the study.  These assessments will specifically include 
evaluation of any areas of depigmentation or rash.  Subjects will also be questioned by the 
investigator at each visit to identify any changes that might represent a drug-induced 
rash/reaction or infection.  Subjects and their caregivers/ informants will be instructed to 
contact the investigator if they see any lesions or other symptoms that might be associated 
with a drug-induced rash/reaction or infection, so such AEs can be reviewed promptly.  
Baseline and on-study blood, DNA, and CSF samples will be taken and stored from all 
subjects.  These samples may be tested in the event that a subject develops AEs that warrant 
further investigation (eg, to test if a subject with a treatment-emergent infection was exposed
to any suspected infective agents before treatment with study drug).  
Safety brain MRI assessments will be performed at Screening, at 6, 12, and 18 months
during the Treatment Phase of the study and at the final Follow-Up Visit.  Additional safety 
MRI scans are to be performed as clinically necessary.  MRI acquisition and interpretation
will be organized centrally to ensure reproducibility and consistency between units involved.  
Full neurological examinations will be performed at Baseline, at 6, 12, and 18 months, and at 
both Follow-Up Visits, by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  The neurological examinations will
include muscle strength testing and assessment of cranial nerves including olfaction as well 
as other parts of the CNS.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments will include the ADAS-cog14, MMSE, and CBB.  
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline 
and at regular intervals throughout the treatment and Follow-Up periods of the study.
An ophthalmic examination will be conducted at Baseline.  If the subject experiences visual 
disturbances during the course of the study, the subject will be referred to a specialist for a 
further ophthalmic examination including, where appropriate, a retinal examination.
Page 1533 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 15 of 139
A number of safety-related withdrawal criteria are specified for the study.
Bioanalytical Methods
Plasma and CSF concentrations of E2609 will be measured by a validated liquid 
chromatography method using tandem mass spectrometry.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based 
enzyme-linked immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF 
Aβ(1-42), tau, and p-tau will be performed using ELISAs.
BACE1 levels and activity may be measured using a customized assay.  Substrates of 
BACE1 inhibition may also be explored using Western blots or other amenable methodology 
if clinical observations warrant and if analytes can be reliably tested in samples collected.
Statistical Methods
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
Study Endpoints
Primary Endpoint

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
Secondary Endpoints
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal subjects 
as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

The derived ADCOMS at 18 months of treatment in mild AD subjects
Exploratory Endpoints
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild AD 
subjects

Total hippocampal volume at 12 and 18 months of treatment in mild AD subjects as 
measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects
Page 1534 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 16 of 139

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild AD
subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months: ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months 
of treatment, and during posttreatment follow-up in MCI/Prodromal and mild AD 
subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 and, 
18 months in MCI/Prodromal and mild AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and 
mild AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild AD subjects
Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.

The Per Protocol Analysis Set is the subset of subjects in the FAS who sufficiently 
comply with the protocol. 

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 serum 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and 
at least 1 posttreatment PD measurement.
Efficacy Analyses
The MCI/Prodromal cohort: This study in the MCI/Prodromal cohort is based on Bayesian 
adaptive design.  Frequent interim analyses will be performed to assess the probability of 
early success and futility and to make early stopping decisions.  Response adaptive 
randomization will be used to update the randomization probability among treatment groups 
at each interim analysis.  Key definitions relevant to the Bayesian aspects of the adaptive 
design are given below.
Study Definitions 

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  
Page 1535 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 17 of 139

ED90: The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria 
if the probability that the ED90 at 18 months of treatment achieves 25% improvement 
over placebo is at least 80%.  Early success is achieved before all MCI/Prodromal
subjects complete 18 months of treatment and can only be determined after at least 
200 MCI/Prodromal subjects have been randomized.  If early success is declared before
full randomization, the randomization of new MCI/Prodromal subjects will stop but 
subjects already randomized into the study will receive the full 18 months of treatment
(following confirmation from the Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if 
the probability that the ED90 is better than placebo by the clinically significant difference 
of 25% is less than 5% at 18 months of treatment.  The statistical futility boundary is 
binding; if the statistical futility boundary is crossed the study will be considered to have 
failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if 
an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild AD cohort: The analysis of the Mild AD cohort is based on the group sequential 
design.  Interim analyses in the Mild AD cohort will only be performed after the 
MCI/Prodromal cohort crosses the early success boundary.  The early efficacy signal based 
on the change from baseline of ADCOMS at 18 months is defined as crossing the 
interim-analysis boundaries for overwhelming efficacy in the mild AD population.  The 
O’Brien-Fleming (OF) boundaries based on Lan-DeMets alpha spending function will be 
used to assess overwhelming efficacy.  The corresponding OF boundaries based on P values 
will be 0.076, 0.0221, and 0.0423 for the first, second, and final analyses, respectively, 
according to 2 planned interim analyses at the 60% and 80% information fraction.
Analysis for the primary endpoint 
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.
For the clinical efficacy data (ie, derived ADCOMS, MMSE, ADAS-cog, etc), subjects will 
be censored at the time of initiation of treatment with AChEIs or memantine, if they were not 
on these medications at the time of Baseline cognitive assessment (Visit 2), and will be 
censored at the time of dose adjustment of AChEIs or memantine if they were already on 
Page 1536 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 18 of 139
stable treatment with these medications at the time of Baseline cognitive assessment 
(Visit 2).  The value of the primary endpoint for censored subjects will be imputed using data 
up to the censoring time and Bayesian longitudinal modeling.
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis. This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have been 
lost to follow up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  These analyses will be performed on 
the FAS as well as the per protocol set.  In case of early success, the conventional analyses 
will also be performed using the data collected before the interim analysis.  
Analysis for the secondary endpoints
The MCI/Prodromal cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild AD cohort
An MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild AD. If there is no treatment group-by-population interaction in the 
overall study, the MMRM analysis will include all subjects (MCI/Prodromal or mild AD) in 
the overall study.  Otherwise, the MMRM analysis will only include subjects in the mild AD 
cohort.  The comparison between placebo and active doses will be performed within mild 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will 
be used to control for multiplicity due to multiple comparisons.
Page 1537 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 19 of 139
Analysis for exploratory endpoints
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild 
AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild AD 
subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in MCI/Prodromal 
subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 months in 
mild AD subjects.  Data from early discontinuations will also be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, 
CBB, and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal 
and mild AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 
4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild AD 
subjects
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months 
in MCI/Prodromal and mild AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 and 
18 months in MCI/Prodromal and mild AD subjects
Page 1538 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 20 of 139
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.  Summary statistics for CSF biomarkers will be assessed for evidence of a dose 
relationship.
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in plasma and 
CSF will be explored graphically and any emergent relationship will be explored through 
population PK/PD modeling.  Additionally, the relationship between CSF exposure to E2609 
and the derived ADCOMS at 18 months, and the relationship between CSF exposure to 
E2609 and the change from baseline for 18 months in the ADAS-cog, the CDR, and the 
MMSE will be explored graphically.  Any emergent relationship will be explored through 
population PK/PD modeling.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT 2 phenotype of 
subjects enrolled in this study.  Further information is in the “Pharmcodynamic, 
Pharmacogenomic, 
and 
Other 
Biomarker 
Assessments” 
section. 
 
Details 
of 
pharmacogenomic testing may be provided and reported separately.
Safety Analyses 
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
Lymphocyte Subsets
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
Page 1539 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 21 of 139
over time by dose.  Serum IgG, IgM, IgA will be measured and summarized in the same 
manner as other laboratory parameters.
Interim Analyses
The MCI/Prodromal cohort
Oversight of the Bayesian interim analyses and response adaptive randomization will be 
conducted by an independent committee that has expertise with Bayesian adaptive design in 
clinical studies.  An unblinded external independent analysis group will provide the interim 
analysis outcomes to the committee at each interim analysis.  The committee will ensure the 
integrity of the interim analysis and response adaptive randomization process through review 
of efficacy data.  In addition, the committee will act in an independent advisory capacity to 
monitor the Bayesian interim analysis outcomes according to the early success and futility 
boundaries prespecified in the protocol.  The committee will not be charged with any subject 
safety issues; this will remain the responsibility of the DSMB.  The DSMB will continue to 
monitor the safety aspects of the study throughout Stage A and Stage B.  The study may be 
stopped for safety at any time.
An interim safety analysis will be conducted when the first 60 MCI/Prodromal subjects have 
completed 12 weeks of treatment.  The first Bayesian adaptive interim analysis will be 
conducted when 100 MCI/Prodromal subjects have been randomized into the study (ie, 
60 subjects from Stage A and the first 40 subjects from Stage B of the study).  Further 
interim efficacy analyses will be conducted after each additional 50 MCI/Prodromal subjects
have been randomized, up to a maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 
200, 250, 300, 350, 400, 450, 500 subjects randomized).  If the study reaches full 
randomization, additional interim analyses will be conducted every 3 months until all
subjects complete 18 months of treatment.  The study will be monitored for futility at each 
interim analysis.  Starting at the 200 subjects’ interim analysis, the study will be monitored 
for success at each interim analysis.  Each interim analysis will be conducted on data for the 
derived ADCOMS.  
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
Page 1540 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 22 of 139
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The Mild AD cohort
A group sequential design will be used for the mild AD cohort.  This design includes 3 looks, 
2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
Interim analyses will be performed after the MCI/Prodromal cohort crosses the early success 
boundary.  The corresponding efficacy boundaries will be 0.076, 0.022, and 0.0423 for the 
first, second, and final analyses, respectively.  If the actual information fraction during the 
interim analyses is different from 60% or 80% at the interim, the efficacy boundaries will be 
adjusted based on the actual information fraction.  If early success in the MCI/Prodromal 
cohort is not achieved before the final analysis that is performed when all subjects have 
completed 18 months treatment, then only a final analysis will be performed in mild AD 
subjects.  In the event of futility in the MCI/Prodromal cohort, an analysis will be performed 
for the mild AD cohort based on the data for mild AD subjects available at that time.  
Adaptive randomization in the MCI/Prodromal cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses
[60 patients in Stage A and the first 40 patients in Stage B]).  Randomization probabilities to 
each treatment group will be updated at each interim analysis, such that the randomization 
probability will be increased for the placebo group and dosage groups that represent the 
potential target dose (ED90), and simultaneously decreased for other active arms.  
Randomization in the Mild AD cohort will remain at a fixed schedule throughout Stage B.
Within the 2 clinical populations (MCI/Prodromal and mild AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or 
memantine or both (yes or no).
Sample Size Rationale
Sample Size Rationale in the MCI/Prodromal cohort
Primary endpoint – derived ADCOMS: The sample size and design characteristics to test the 
hypothesis for the primary objective based on the primary endpoint were determined by 
means of simulations.  Extensive study simulations have shown that a total of 500 subjects 
will be sufficient to demonstrate that the most likely ED90 dose achieves a 25% improvement 
over placebo with a probability of at least 80% in the interim and final analyses.  There is at 
least a 90% probability of study success for the dose response scenarios where treatment was 
considered to have a clinically meaningful treatment effect.  Simulations have also shown 
that if there is no obvious dose effect, the probability of falsely claiming superiority to 
placebo is at most 5%.  
Page 1541 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 23 of 139
For each of the 4 treatment groups (3 active doses and placebo), the final number of subjects 
per group will differ depending on the observed interim treatment responses.  
vMRI: The null hypothesis is that there is no difference between active dose and placebo.  
There are 3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is 
that at least 1 null hypothesis is false (1-sided).  The null hypotheses will be tested using 
Dunnett’s method with 1-sided alpha of 0.05.  The statistical power was estimated through 
simulation for a moderate dose-response assumption that the percent reduction in change 
from baseline of total hippocampal volume compared with placebo would be 15%, 20%, and 
25% corresponding to the 3 doses, respectively.  The estimated power for actual planned 
study sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  
Under a stronger dose-response assumption (ie, the percent reduction in change from 
baseline of total hippocampal volume compared with placebo is twice as much as that in the 
moderate dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET: The null and alternative hypotheses and statistical test are the same as those
for vMRI.  To estimate the sample size for the amyloid PET imaging subgroup at 18 months, 
a common SD of change from baseline was estimated at 0.33 and a reasonable mean 
difference between treatment and placebo was estimated as 0.25 (standardized uptake value 
ratio [SUVR]).  Assuming a moderate dose-response, the best dose would achieve a 
difference of 0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 
and 0.15 (SUVR), respectively, it would require a total of 100 subjects from all 4 arms at 
18 months to achieve 80% power.
Sample Size Rationale for the Mild AD Cohort
ADCOMS at Month 18: The null hypothesis is that there is no difference between active 
dose and placebo.  There are 2 null hypotheses corresponding to 2 active doses.  The 
alternative hypothesis is that at least 1 null hypothesis is false.  The null hypotheses will be 
tested using Dunnett’s test with 2-sided alpha of 0.05 as described for the mild AD cohort in 
the secondary analysis section.  The statistical power was estimated through simulation for 
the dose-response assumption that the percent reduction in change from baseline of 
ADCOMS at 18 months compared with placebo would be 33% and 50% corresponding to 
the 2 doses, respectively.  The estimated power for the actual planned 200 mild AD subjects 
is at least 80% assuming a 2-sided alpha of 0.05.
Page 1542 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 24 of 139
3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................29
5
ETHICS............................................................................................................................32
5.1
Institutional Review Boards/Independent Ethics Committees ..............................32
5.2
Ethical Conduct of the Study.................................................................................32
5.3
Subject Information and Informed Consent...........................................................33
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................34
7
INTRODUCTION ...........................................................................................................35
7.1
Nonclinical and Clinical Safety Data.....................................................................36
8
STUDY OBJECTIVES....................................................................................................39
8.1
Primary Objectives.................................................................................................39
8.2
Secondary Objectives.............................................................................................39
8.3
Exploratory Objectives ..........................................................................................39
9
INVESTIGATIONAL PLAN..........................................................................................41
9.1
Overall Study Design and Plan..............................................................................41
9.1.1
Prerandomization Phase...............................................................................44
9.1.1.1
Screening Period..................................................................................44
9.1.1.2
Baseline Period ....................................................................................46
9.1.2
Randomization Phase...................................................................................46
9.1.2.1
Treatment Period..................................................................................46
9.1.2.2
Early Discontinuation ..........................................................................47
9.1.2.3
Follow up .............................................................................................47
9.2
Discussion of Study Design, Including Choice of Control Groups.......................47
9.2.1
Overview......................................................................................................47
9.2.2
Rationale for Study Population....................................................................48
9.2.3
Rationale for the Use of Bayesian Adaptive Design ...................................49
9.2.4
Rationale for Clinical Endpoints..................................................................49
9.2.5
Rationale for Biomarkers.............................................................................51
9.2.5.1
Overall Rationale .................................................................................51
9.2.5.2
Soluble Biomarkers in CSF .................................................................51
9.2.5.3
Amyloid PET .......................................................................................52
9.2.5.4
vMRI....................................................................................................52
9.2.6
Clinical Risks and Mitigation Strategy........................................................53
9.3
Selection of Study Population................................................................................54
Page 1543 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 25 of 139
9.3.1
Inclusion Criteria .........................................................................................55
9.3.2
Exclusion Criteria ........................................................................................56
9.3.3
Removal of Subjects from Therapy or Assessment.....................................59
9.4
Treatments..............................................................................................................62
9.4.1
Treatments Administered.............................................................................62
9.4.2
Identity of Investigational Product...............................................................63
9.4.2.1
Chemical Name, Structural Formula of E2609....................................63
9.4.2.2
Comparator Drug .................................................................................64
9.4.2.3
Labeling for Study Drug......................................................................64
9.4.2.4
Storage Conditions...............................................................................64
9.4.3
Method of Assigning Subjects to Treatment Groups...................................64
9.4.4
Selection of Doses in the Study...................................................................65
9.4.5
Selection and Timing of Dose for Each Subject..........................................66
9.4.6
Blinding........................................................................................................67
9.4.7
Prior and Concomitant Therapy...................................................................67
9.4.8
Treatment Compliance.................................................................................69
9.4.9
Drug Supplies and Accountability...............................................................69
9.5
Study Assessments.................................................................................................71
9.5.1
Assessments.................................................................................................71
9.5.1.1
Demography.........................................................................................71
9.5.1.2
Baseline Assessments ..........................................................................71
9.5.1.2.1
Medical History and Physical Examinations.................................71
9.5.1.2.2
Psychometric Assessments ............................................................72
9.5.1.2.3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................72
9.5.1.3
Efficacy Assessments...........................................................................73
9.5.1.3.1
Psychometric Assessments ............................................................73
9.5.1.3.2
Volumetric MRI.............................................................................75
9.5.1.3.3
Cerebrospinal Fluid Sampling .......................................................75
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................75
9.5.1.4.1
Pharmacokinetic Assessments .......................................................75
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................76
9.5.1.5
Safety Assessments..............................................................................76
9.5.1.5.1
Adverse Events and Other Events of Interest ................................77
9.5.1.5.2
Serious Adverse Events and Other Events of Interest ...................79
9.5.1.5.3
Laboratory Measurements .............................................................80
Page 1544 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 26 of 139
9.5.1.5.4
Vital Signs and Weight Measurements..........................................82
9.5.1.5.5
Physical Examinations...................................................................82
9.5.1.5.6
Electrocardiograms ........................................................................82
9.5.1.5.7
Safety MRI.....................................................................................83
9.5.1.5.8
Dermatological Assessment...........................................................84
9.5.1.5.9
Neurological Examination .............................................................84
9.5.1.5.10
Pregnancy Test...............................................................................84
9.5.1.5.11
Columbia Suicide Severity Rating Scale.......................................85
9.5.1.5.12
Biomarker Samples........................................................................85
9.5.2
Schedule of Procedures/Assessments ..........................................................85
9.5.2.1
Schedule of Procedures/Assessments ..................................................85
9.5.2.2
Description of Procedures/Assessments Schedule...............................93
9.5.3
Appropriateness of Measurements...............................................................94
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................94
9.5.4.1
Reporting of Serious Adverse Events..................................................94
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................95
9.5.4.3
Reporting of Other Events of Interest..................................................96
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................96
9.5.4.3.2
Reporting of Significant Laboratory Abnormality ........................96
9.5.4.3.3
Reporting of Study-Specific Events...............................................97
9.5.4.4
Expedited Reporting ............................................................................97
9.5.4.5
Breaking the Blind...............................................................................97
9.5.4.6
Regulatory Reporting of Adverse Events ............................................98
9.5.5
Completion/Discontinuation of Subjects.....................................................98
9.5.6
Abuse or Diversion of Study Drug ..............................................................98
9.5.7
Confirmation of Medical Care by Another Physician .................................99
9.6
Data Quality Assurance .........................................................................................99
9.6.1
Data Collection ............................................................................................99
9.6.2
Clinical Data Management ..........................................................................99
9.7
Statistical Methods...............................................................................................100
9.7.1
Statistical and Analytical Plans..................................................................100
9.7.1.1
Study Endpoints.................................................................................100
9.7.1.1.1
Primary Endpoint.........................................................................100
9.7.1.1.2
Secondary Endpoints ...................................................................100
9.7.1.1.3
Exploratory Endpoints .................................................................100
Page 1545 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 27 of 139
9.7.1.2
Definitions of Analysis Sets...............................................................101
9.7.1.3
Subject Disposition............................................................................101
9.7.1.4
Demographic and Other Baseline Characteristics .............................102
9.7.1.5
Prior and Concomitant Therapy.........................................................102
9.7.1.6
Efficacy Analyses ..............................................................................103
9.7.1.6.1
Primary Efficacy Analysis...........................................................104
9.7.1.6.2
Secondary Efficacy Analyses ......................................................105
9.7.1.6.3
Exploratory Efficacy Analyses ....................................................105
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................106
9.7.1.7.1
Pharmacokinetic Analyses...........................................................106
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.......................................................................................106
9.7.1.8
Safety Analyses..................................................................................107
9.7.1.8.1
Extent of Exposure.......................................................................107
9.7.1.8.2
Adverse Events ............................................................................107
9.7.1.8.3
Laboratory Values........................................................................109
9.7.1.8.4
Vital Signs....................................................................................109
9.7.1.8.5
Electrocardiograms ......................................................................110
9.7.1.8.6
Other Safety Analyses..................................................................110
9.7.2
Determination of Sample Size ...................................................................110
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort.......................110
9.7.2.2
Sample Size Rationale for the Mild AD Cohort................................111
9.7.3
Interim Analysis.........................................................................................112
9.7.4
Other Statistical/Analytical Issues .............................................................113
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................114
10
REFERENCE LIST .......................................................................................................115
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....119
11.1
Changes to the Protocol .......................................................................................119
11.2
Adherence to the Protocol....................................................................................119
11.3
Monitoring Procedures.........................................................................................119
11.4
Recording of Data................................................................................................120
11.5
Identification of Source Data...............................................................................120
11.6
Retention of Records............................................................................................121
11.7
Auditing Procedures and Inspection....................................................................121
11.8
Handling of Study Drug.......................................................................................121
11.9
Publication of Results ..........................................................................................122
11.10 Disclosure and Confidentiality ............................................................................122
Page 1546 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 28 of 139
11.11 Discontinuation of Study .....................................................................................122
11.12 Subject Insurance and Indemnity.........................................................................122
12
APPENDICES ...............................................................................................................123
LIST OF IN-TEXT TABLES
Table 1
Study Conduct Actions for Lymphocyte Subset Absolute Counts............60
Table 2
Study Conduct Actions for Lymphocyte Subset Absolute Counts and 
Infection.....................................................................................................61
Table 3
Predicted Steady State Plasma PK Parameters and CSF Amyloid β 
Reduction From Baseline...........................................................................65
Table 4
Clinical Laboratory Tests...........................................................................81
Table 5
Lymphocyte Subtyping..............................................................................81
Table 6
Schedule of Procedures/Assessments in Study 202:  Prerandomization 
Phase (Visit 1 and Visit 2) .........................................................................86
Table 7
Schedule of Procedures/Assessments in Study 202:  Randomization 
Phase (Visit 3 through Visit 20).................................................................89
Table 8
Summary of Blood and CSF Sample Volumes..........................................93
LIST OF IN-TEXT FIGURES
Figure 1
Design of Study 202...................................................................................42
Figure 2
Assessments to be Performed at Screening by Tier...................................45
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................123
Appendix 2
List of Permitted and Prohibited Prior/Concomitant Medications ..........125
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 135
Page 1547 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 29 of 139
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
A
amyloid β
Aβ(1-x)
amyloid β (1-x) (ie, the amyloid β monomer from amino acid 1 to 
x [eg 1-42])
AChEI
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-cog
Alzheimer’s Disease Assessment Scale - cognitive subscale
ADCOMS
Alzheimer’s Disease Composite Score
AE
Adverse Event
ApoE
Apolipoprotein E
AUC
area under the concentration x time curve 
AUC(0-24h)ss
area under the concentration x time curve at steady state from 
time zero to 24 hours
BACE1
Beta-amyloid converting enzyme 1
BP
blood pressure
bpm
beats per minute
CBB
CogState Brief Battery
CBP
childbearing potential
CDR
Clinical Dementia Rating
CES2
carobxyesterase-2
CFR
Code of Federal Regulations
Cmax,ss
maximum plasma concentration at steady state
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
Css,av
average steady-state concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
CYP
cytochrome P450
dMax
Maximum effective dose
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
Page 1548 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 30 of 139
Abbreviation
Term
ED90
lowest effective dose that achieves 90% of the greatest treatment 
effect 
ELISA
enzyme-linked immunosorbent assay
FAQ
Functional Assessment Questionnaire
(also known as the 
Functional Activities Questionnaire) 
FAS
Full Analysis Set
FDA 
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCVAb
hepatitis C virus antibody
HSV
herpes simplex virus
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ID
identifier
IEC
Independent Ethics Committee
Ig
immunoglobulin (eg, IgA, IgG, IgM)
IRB
Institutional Review Board
ISLT
International Shopping List Task
IxRS
interactive voice and web response system
LLN
lower limit of normal
LNH
low/normal/high
LP
lumbar puncture
MAD
multiple ascending dose
MCI
mild cognitive impairment
MCI/Prodromal
Mild Cognitive Impairment due to Alzheimer’s Disease/ 
Prodromal Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
mild AD
mild dementia due to Alzheimer’s Disease
MMRM
mixed-effects model with repeated measures
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NAT2
N-acetyltransferase 2
NIA-AA
National Institute on Aging-Alzheimer’s Association
Page 1549 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 31 of 139
Abbreviation
Term
OF
O’Brien-Fleming 
PD
Pharmacodynamic(s)
PET
positron emission tomography
PGx
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PP
per protocol
PRN
Pro re nata
PT
preferred term
p-tau
phosphorylated-tau
QD
once daily
QTc
corrected QT interval
QTcF
QTc interval calculated using Fridericia’s formula
R
randomization
SAD
single ascending dose
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SUVR
standardized uptake value ratio
TB
tuberculosis
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
t-tau
total tau
ULN
upper limit of normal
UNS
unscheduled
vMRI
volumetric magnetic resonance imaging
WHO DD
World Health Organization Drug Dictionary
β-hCG
beta-human chorionic gonadotropin
Study References: On first use, the full study code will be used (eg, E2609-G000-202) with 
a shortened form in brackets (Study 202); thereafter, the shortened form is used.
Page 1550 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 32 of 139
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 Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice [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 associate [CRA][s], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC (or if regionally required, the investigator and the relevant IRB via 
the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:  

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (CFR) (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
Page 1551 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 33 of 139

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union country.  All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved European Union member states.  

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator, or designee, must 
explain to each subject and the identified caregiver or informant, 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 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 
the identified caregiver or informant 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 and the identified 
caregiver or informant, and after the subject 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 at the Screening Visit before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
The identified caregiver or informant should also consent to supporting the subject’s 
participation in the study and will be provided with a separate written ICF for his or her 
participation in the study, to be signed before he or she participates in any further aspects of 
the study.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject and identified caregiver or 
informant must sign an approved ICF before study participation.  The form must be signed 
and dated by the appropriate parties.  The original, signed ICF for each subject and identified 
caregiver or informant will be verified by the sponsor and kept on file according to local 
procedures at the site.  The subject and the identified caregiver or informant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.  The communication of this 
information should be documented.
Page 1552 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 34 of 139
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 125 investigational sites globally (25 sites in the United States for 
Stage A and 125 sites globally for Stage B).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the
Investigator Study File or the Regulatory Binder provided to each site.
Page 1553 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 35 of 139
7
INTRODUCTION
At this time, there is no cure for Alzheimer’s disease (AD), no known way of slowing down 
the progression of this disease, and no approved treatment available to reverse the 
deterioration.  There is, therefore, an urgent unmet medical need for drugs that slow or 
prevent disease progression.  Beta-amyloid converting enzyme 1 (BACE1) is a key enzyme 
responsible for the production of amyloid β (Aβ) peptides and plaque formation, and several 
reports have described elevated levels of BACE1 in AD brains (Coulson, et al., 2010, Lu, et 
al., 2012).  Once amyloid plaques form, Aβ causes BACE1 levels to increase further, thus 
accelerating Aβ generation and plaque growth via a positive feedback loop.  Therefore, 
BACE1 is a promising target for modifying or treating AD.  
It is now widely accepted that mild cognitive impairment (MCI) due to AD and mild AD 
dementia are stages on a single disease spectrum, which follows an Alzheimer’s pathological 
cascade.  Recent consensus papers from the international workgroups of the National 
Institute on Aging-Alzheimer’s Association (NIA-AA), have endorsed this hypothesis 
(Albert, et al., 2011; Jack, et al., 2011; McKhann, et al., 2011; Sperling, et al., 2011).  
From a clinical standpoint, demonstration of an effect on slowing disease course is hampered 
by the lack of sensitive tools for detecting relatively small changes in progression or 
treatment effect especially in early disease.  In addition, drugs that are expected to slow 
disease progression require longer study durations to ensure adequate separation from 
placebo.  These challenges have resulted in the use of biomarkers as surrogates for clinical 
effect in Phase 2 studies, in order to facilitate the development process for disease modifying 
agents.  However, subsequent Phase 3 AD studies based solely on biomarker findings in 
Phase 2 have failed to show clinical effect, due, in part, to the fact that biomarkers may not 
predict clinical outcomes for potential disease modifying agents.  These findings underscore 
the need for innovative approaches to clinical study design for measuring the effect of 
treatment.
E2609 is a novel, small-molecule BACE1 inhibitor.  Preclinical studies have shown that after 
oral dosing, E2609 inhibits the production of Aβ40 and Aβ42 in brain (rat and guinea pig) 
and in cerebrospinal fluid (CSF) and plasma (rat, guinea pig, and monkey).  In humans, 
E2609 has been shown to inhibit BACE1 enzyme activity in CSF and lower the levels of Aβ, 
including amyloid beta monomer from amino acid 1 to x (Aβ[1-x]), Aβ(1-40) and Aβ(1-42), 
in CSF both in vitro and in vivo.  See the Investigator’s Brochure for additional information.  
The target indication for E2609 is therefore treatment and disease modification of AD.  
The present clinical study represents the sole Phase 2 study for the E2609 program, and is 
designed to establish Proof of Concept in subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease/Prodromal Alzheimer’s Disease (referred to as MCI/Prodromal
throughout the protocol).  The study also allows investigation of efficacy in subjects with
mild dementia due to Alzheimer’s Disease (referred to as mild AD throughout the protocol)
to determine whether the effects of E2609 in this later stage population are comparable with 
those established in the MCI/Prodromal population within this same study.  In the 
MCI/Prodromal population, Bayesian response adaptive randomization design is used with 
Page 1554 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 36 of 139
frequent interim analyses to continually update randomization allocation based on emerging 
clinical endpoint data.  This approach allows for ongoing assessment of drug futility or 
evidence of early success and can mitigate the risks associated with larger and longer studies 
required to demonstrate clinical efficacy by leading to more efficient study termination or 
early advancement to a Phase 3 program.  Results from this study will guide both the 
decision to move into Phase 3 development and the selection of the dose strengths to be taken 
into Phase 3.  Moreover, this study is intended to be supportive for registration in the 
MCI/Prodromal population.  
In the MCI/Prodromal population, this study will compare placebo and 3 oral doses of E2609 
(5 mg, 15 mg and 50 mg) administered once daily (QD) for 18 months.  In the mild AD 
population, this study will compare placebo and 2 oral doses of E2609 (15 mg and 50 mg) 
administered QD for 18 months.  To date, the longest duration of dosing with E2609 is 
14 days (multiple ascending dose [MAD] Study E2609-A001-002 [Study 002]).  
This study (E2609-G000-202 [Study 202]) will comprise 2 stages: Stage A and Stage B.  
Stage A will include an interim evaluation of the safety and tolerability of chronic dosing 
with E2609 in the United States sites only, before expanding enrollment to a larger and more 
global population of subjects in Stage B.  This design will allow close monitoring of safety 
by an independent data safety monitoring board (DSMB), including a formal safety review as 
soon as the first 60 randomized subjects have completed 12 weeks of treatment or have 
withdrawn from the study.  The study also includes a number of exclusion criteria, specific 
blinded safety monitoring procedures and safety withdrawal criteria in light of the preclinical 
and clinical safety data collected to date following administration of E2609.  
7.1
Nonclinical and Clinical Safety Data
The toxicity of E2609 has been evaluated in oral repeated-dose toxicology studies of up to 
26 weeks duration in rats and 39 weeks in cynomologus monkeys.  Nonclinical findings of 
note include immunologic-related findings at 30 mg/kg and above in monkeys (including 
1 cytomegalovirus-related death at 60 mg/kg).  An additional completed monkey 
immunology study suggested that lymphocytes and lymphocyte subsets may be suitable 
markers to monitor potential immunotoxicity or immunomodulation by E2609 in a clinical 
setting.  Further details of the nonclinical data to date with E2609 can be found in the 
Investigator’s Brochure.  
The clinical program to date includes 6 Phase 1 studies:  
Study E2609-A001-001 (Study 001) was a randomized, double-blind and placebo-controlled, 
single ascending dose (SAD) study that investigated doses ranging from 5 to 800 mg in 
healthy adult subjects (aged 30 to 55 years) and elderly subjects (50 mg dose only, aged 65 to 
85 years).  
Study 002 was a randomized, double-blind and placebo-controlled MAD study in healthy 
male and female subjects aged 50 to 85 years.  CSF was collected before and following the 
Page 1555 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 37 of 139
14 days of dosing so as to assess the pharmacokinetic (PK) levels of E2609 and the 
pharmacodynamic (PD) effects on BACE activity and Aβ levels.
Study E2609-A001-003 (Study 003) was a single-center, open label study in healthy subjects 
investigating the effects of drug-drug interactions by itraconazole, rifampin, and donepezil on 
the PK properties of E2609.  It also investigated the effects of E2609 on the PK properties of 
digoxin.  The clinical phase has been completed and reporting is in progress.  
Study E2609-A001-005 was an open label, single-dose study to determine the metabolism 
and elimination of [14C]E2609 in healthy male subjects (aged 18 to 55 years).
Study E2609-A001-007 (Study 007) was a single-center, open label, randomized, 3-treatment 
crossover study of single oral doses of a capsule formulation of E2609 under fasted 
conditions and a tablet formulation administered under fed and fasted conditions in healthy 
subjects to evaluate their relative bioavailability.
Study E2609-A001-101 (Study 101) was a randomized, double-blind, placebo-controlled, 
Bayesian adaptive design study in adults aged 50 to 85 years with subjective memory 
complaints and who qualified as having MCI or mild AD.  
The safety data from the SAD and MAD studies are discussed below, with particular focus 
on the context of the nonclinical findings with E2609.  The clinical safety data are described 
in more detail in the Investigator’s Brochure.  
In the SAD study, single doses were well tolerated.  All treatment-emergent adverse events 
(TEAEs) were mild to moderate in severity, with no severe TEAEs.  There were 
no dose-related trends in the incidence of AEs among subjects treated with E2609.  In elderly 
subjects treated with 50 mg of E2609, tolerability was comparable to younger subjects.  
There were no specific AEs in elderly subjects which were evidently more frequent than in 
younger subjects.  No serious adverse events (SAEs) were reported, and there were 
no clinically significant changes in mean laboratory safety parameters, vital signs, or 
electrocardiogram (ECG) parameters.  The 800 mg (maximum) dose was associated with a 
small increase of QTc interval calculated using Fridericia’s formula (QTcF) from baseline 
(14.9 msec at 4 hours postdose), consistent with nonclinical findings.  Overall the data 
suggested that a single dose of E2609 might reduce some lymphocyte subsets (eg, CD4 
[T helper cells], CD8 [cytotoxic T cells]) but the effects were highly variable across doses 
and the findings were not conclusive.  There were no trends to suggest that E2609 altered 
immunoglobulin (Ig) levels.  There were no clinical manifestations in terms of primary 
infections or relapse of latent infections in subjects who received single doses of E2609.  A
single dose of E2609 up to 800 mg is not considered to pose clinical safety concerns with 
regard to immune function.
In the MAD study, AEs of interest included relapse of orolabial herpes, viral respiratory tract 
infection, drug rash, and abnormal dreams.  More details are available in the Investigator’s 
Brochure. In summary, E2609 administered at doses of 200 and 400 mg was associated with 
reductions in CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) counts at 
Day 8.  These reductions were more clearly evident by Day 15, consistent with a treatment 
Page 1556 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 38 of 139
by time interaction in the statistical analysis.  There was evidence that the lower doses of 
50 to 100 mg also caused some reduction in CD4 lymphocyte counts by Day 15.  Doses 
above 100 mg appeared to be associated with greater reductions in CD4 and CD8 
lymphocyte counts, which occurred earlier in the treatment period compared with the effects 
of 25 to 100 mg doses.  These effects on lymphocyte counts gradually resolved from Day 20 
to Day 35, which were 6 and 21 days, respectively, after administration of the last dose of 
E2609 on Day 14.  Reductions in CD4 and CD8 lymphocyte counts at doses of 200 and 
400 mg to a level close to or less than the lower limit of normal (LLN) could be associated 
with increased risk of developing relapse of orolabial herpes or other infections.
In Study 003, a drug-drug interaction study, PK results showed that itraconazole (a potent 
inhibitor of cytochrome P450 [CYP] 3A4 and carobxyesterase-2 [CES2]) caused a mild 
increase (by approximately 70%) of the area under the concentration x time curve (AUC) of 
E2609.  Rifampin (a potent CYP3A4 inducer) caused a mild decrease (by approximately 
20%) of the AUC of E2609.  Donepezil (a moderate CES2 inhibitor) caused a mild increase 
(by approximately 20%) of the AUC of E2609 when coadministered with E2609 but not 
when dosed at least 2 hours apart from E2609.  E2609 (which inhibits the P-glycoprotein 1 
transporter) did not affect the PK properties of digoxin.  Nonclinical studies also indicated 
that other CYP pathways apart from CYP3A4 would not be major pathways of metabolism 
of E2609.  Based on these results, it is not considered necessary to impose restrictions during 
E2609 treatment on the use of concomitant medications that may be CYP3A4 inhibitors or 
other CYP enzymes inhibitors, or CES2 inhibitors.  Similarly, it was also not considered 
necessary to restrict the use of concomitant medications which are inducers of CYP450 
enzymes.
Page 1557 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 39 of 139
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives are:  
1. To evaluate the efficacy of daily dosing with 3 doses of E2609 compared with placebo by 
establishing the lowest effective dose that achieves 90% of the greatest treatment effect 
(ED90) for E2609 on the derived Alzheimer’s Disease Composite Score (ADCOMS) at 
18 months of treatment in subjects with MCI/Prodromal
2. To assess the safety (including immunological and hematological parameters) and 
tolerability of daily dosing with E2609 in MCI/Prodromal subjects and in subjects with 
mild AD
8.2
Secondary Objectives
The secondary objectives are:  
1. To evaluate the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in MCI/Prodromal subjects, as measured by volumetric 
magnetic resonance imaging (vMRI) 
2. To evaluate the effect of E2609 compared with placebo on Aβ(1-x) in CSF after 4 weeks 
and 18 months of treatment in MCI/Prodromal subjects
3. To evaluate the efficacy of E2609 compared with placebo on the derived ADCOMS at 
18 months in mild AD subjects
8.3
Exploratory Objectives
The exploratory objectives are:  
1. To explore the effect of E2609 compared with placebo on the derived ADCOMS 
following 12 months of treatment in MCI/Prodromal and mild AD subjects
2. To explore the effect of E2609 compared with placebo on total hippocampal atrophy at 
12 and 18 months of treatment in mild AD subjects, as measured by vMRI
3. To explore the effects of E2609 compared with placebo on Aβ(1-42) in CSF after 
4 weeks and 18 months of treatment in MCI/Prodromal subjects
4. To explore the effects of E2609 compared with placebo on Aβ(1-x) and Aβ (1-42) in CSF 
after 4 weeks and 18 months of treatment in mild AD subjects
Page 1558 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 40 of 139
5. To explore the effects of E2609 compared with placebo on clinical status at various time 
points during 18 months of treatment, and during post treatment follow-up, in 
MCI/Prodromal and mild AD subjects, by assessment of:  
a.
The Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
b. The Clinical Dementia Rating (CDR) scale
c.
The Mini-Mental State Examination (MMSE)
d. The CogState Brief Battery (CBB)
e.
The Functional Assessment Questionnaire (FAQ; (also known as the Functional 
Activities Questionnaire)
f.
The International Shopping List Task (ISLT)
6. To explore the effects of E2609 compared with placebo on various biomarkers in 
MCI/Prodromal and mild AD subjects.  Biomarkers to be explored include:  
a.
CSF biomarkers of neurodegeneration (eg, tau, phosphorylated-tau [p-tau]) after
18 months of treatment
b.
Plasma and CSF amyloid, and CSF BACE1 measurements during 18 months of 
treatment and during post treatment follow-up
c.
vMRI measurements including left and right hippocampal volume, whole brain 
volume, and total ventricular volume at 6, 12, and 18 months of treatment and during 
post treatment follow-up 
d.
Brain amyloid levels at 18 months as measured by amyloid positron emission 
tomography (PET)
7. To characterize the population PK of E2609 in MCI/Prodromal and mild AD subjects, 
and 
to 
examine 
the 
effect 
of 
intrinsic 
and 
extrinsic 
factors 
(including 
N-acetyltransferase 2 [NAT2] phenotype) on the PK 
8. To explore the relationship between the treatment effects of E2609 on the ADCOMS and 
its effects on CSF amyloid, CSF BACE1, CSF tau, and vMRI in MCI/Prodromal and 
mild AD subjects
Page 1559 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 41 of 139
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study 202 is a multicenter placebo-controlled, double-blind, parallel-group, randomized, 
dose-finding study in subjects with MCI/Prodromal AD or mild AD.  
A common set of inclusion criteria, consistent with the NIA-AA clinical research criteria for 
MCI due to AD or mild AD, will be required for all subjects.  In addition, the MCI due to 
AD population will also qualify under the research criterion for “Prodromal AD.”  As the 
non-demented subjects will fulfill the criteria for both MCI due to AD and Prodromal AD 
they will be identified as MCI/Prodromal subjects in this protocol. 
The diagnosis of 
MCI/Prodromal AD or mild AD will be based on both clinical and biological (ie, 
confirmation of amyloid load in the brain) criteria.  
The study will be conducted in 2 stages, Stage A and Stage B.  Stage A will include an
interim evaluation of the safety and tolerability of chronic dosing with E2609 (at least 
12 weeks) in MCI/Prodromal subjects, before expanding enrollment to include a larger 
population of MCI/Prodromal subjects in Stage B (maximum of approximately 500 subjects 
across both stages).  In addition, during Stage B of the study, subjects with mild AD will be 
recruited into a separate cohort (approximately 200 subjects).  All MCI/Prodromal subjects 
will be included in the primary efficacy evaluation irrespective of whether they were 
recruited into Stage A or Stage B of the study.  
Both Stage A and Stage B of the study will consist of 2 phases: Prerandomization and 
Randomization.  The Prerandomization Phase (up to 60 days) will consist of a Screening 
Visit and a Baseline Visit.  Screening assessments will be organized into 4 tiers; see 
Section 9.5.2.2, Table 6, and Figure 2.  All screening assessments must be completed, and 
eligibility to continue to the Baseline Period confirmed, before any baseline assessments 
commence.  Following successful completion of the Prerandomization Phase, eligible 
subjects will be randomized and will enter the Randomization Phase, which will consist of 
2 periods: Treatment (78 weeks) and Follow-Up (post last dose; 12 weeks).
MCI/Prodromal subjects will be randomized to 4 treatment groups (E2609 at 3 doses or 
placebo, with an initial ratio of 1:1:1:1) and this recruitment will take place during both 
Stage A and Stage B.  Bayesian adaptive randomization will be used in Stage B in the 
MCI/Prodromal cohort.  Subjects with mild AD who are recruited in Stage B will be 
randomized to 3 treatment groups (E2609 at 2 doses or placebo).
An overview of the study design is presented in Figure 1.
Page 1560 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 42 of 139
Figure 1
Design of Study 202
R = randomization.
Page 1561 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 43 of 139
Stage A
Stage A of the study will be limited to approximately 25 clinical centers in the United States.  
Stage A will enroll 60 eligible MCI/Prodromal AD subjects who will be randomized 1:1:1:1 
to 4 treatment groups.  There will be no Bayesian adaptation during Stage A of the study.  In 
addition to the placebo group, 3 doses of E2609 will be used to reduce CSF Aβ levels by 
approximately 25% (5 mg), 50% (15 mg), and 75% (50 mg) from baseline, respectively, at 
steady state.  PK/PD modeling shows these doses should achieve these targets when 
administered QD with food and will be confirmed or adjusted based on the 4-week 
assessment of CSF Aβ(1-x) (see Section 9.4.4).
During Stage A, safety data will be monitored in a blinded fashion on a regular basis.  In 
addition, approximately every 3 months from the time the first subject is randomized during 
Stage A of the study, an independent DSMB (including at least 1 immunologist) will review 
all safety data in an unblinded manner.  The DSMB will make recommendations to Eisai 
after each review as to whether any change(s) to the study are necessary.  Unless the DSMB 
recommends otherwise, randomization of subjects into Stage A of the study will continue 
until 60 MCI/Prodromal subjects have been randomized and dosed.  
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B of the study (see Section 9.4.4).
Once 60 MCI/Prodromal subjects in Stage A have completed at least 12 weeks of treatment, 
an interim safety analysis will be conducted by Eisai and the DSMB.  Subjects in Stage A 
will continue study drug while the DSMB reviews all the available safety data, but 
randomization of additional subjects will not take place (ie, recruitment into Stage B will not 
commence) until the safety analysis is completed by the DSMB.  At the time of this interim 
safety analysis, some subjects will have more than 12 weeks of safety data.  
Stage B
Stage B of the study will start after the DSMB safety review of Stage A has shown 
acceptable safety and tolerability of E2609 and after the doses of E2609 to be used in 
Stage B are confirmed.  Based on data from Stage A, the protocol will be reviewed and may 
be amended before beginning Stage B.  Safety data from Stage B will continue to be 
reviewed by the DSMB (approximately every 3 months) until recruitment in the study is 
completed; following this the DSMB will meet approximately every 6 months.
Stage B of the study will be conducted globally and will enroll, randomize, and dose up to an 
additional 440 eligible MCI/Prodromal subjects; the final total number will depend upon 
whether the prespecified criteria for either early success or futility are met.  In addition, a 
separate cohort of approximately 200 mild AD subjects will be randomized and dosed during 
Stage B.
Page 1562 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 44 of 139
Both population cohorts will include separate placebo groups.  The MCI/Prodromal cohort 
will include 3 doses of E2609 (5 mg, 15 mg, and 50 mg QD), whereas the mild AD cohort 
will only include 2 doses of E2609 (15 mg and 50 mg QD).  
Bayesian adaptive randomization will be used in the MCI/Prodromal cohort during Stage B 
of the study.  The first 40 MCI/Prodromal subjects recruited into Stage B will be randomized 
according to a fixed schedule (1:1:1:1; placebo: 5 mg E2609: 15 mg E2609: 50 mg E2609) 
and the remaining subjects in the MCI/Prodromal cohort will be randomized according to 
response adaptive randomizations based on the ADCOMS results using the Bayesian interim 
efficacy analyses.  The mild AD subjects will be randomized according to a fixed schedule 
(1:1:1 placebo; 15 mg E2609; 50 mg E2609) throughout Stage B of the study.
Interim efficacy analyses are planned and are discussed in Section 9.7.3.
9.1.1
Prerandomization Phase
The Prerandomization Phase includes a Screening Visit and a Baseline Visit.  All 
Screening Visit assessments must be completed and eligibility to progress must be confirmed 
before any Baseline Visit assessments are performed.  All Screening Visit and Baseline Visit 
assessments must be completed within 50 days and a window of 7 to 10 days is to be 
observed between the completion of all Baseline Visit assessments and randomization into 
the study at Visit 3.  Thus, the Prerandomization Phase will last for up to 60 days.  The series 
of assessments conducted during this phase will determine eligibility for randomization into 
the study.  
Inclusion criteria are discussed in Section 9.1 and detailed in Section 9.3.1.  Before
randomization the clinician will provide a judgment on the classification of a subject as either 
MCI/Prodromal (eligible for Stage A and Stage B) or likely mild AD (eligible for Stage B 
only).  This judgment may be discussed and reviewed with the Sponsor or Sponsor’s 
representative, as necessary.
9.1.1.1
Screening Period
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 caregiver or informant, and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  No subject will undergo any further study procedures unless this informed 
consent has been obtained from both the subject and the caregiver or informant.  The 
caregiver or informant needs to be present at this visit.
Study site personnel will interview the subject and caregiver or informant to obtain 
demographic and clinical information as described in Table 6, and will review inclusion and 
exclusion criteria as described in Sections 9.3.1 and 9.3.2 and perform any required 
assessments in order to complete these criteria.  Prior medications and medications currently 
being taken by the subject will be reviewed (see Section 9.4.7).  The Screening Disposition
Page 1563 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 45 of 139
electronic case report form (eCRF) page must be completed to indicate whether the subject is 
eligible to participate in the study and to provide reasons for screen failure, if applicable.
Clinical assessments for eligibility will be conducted during the Screening Visit as described 
in Table 6 and Figure 2.  Every effort should be made to conduct these assessments in the 
morning, but if this is not possible, they should be conducted at the same time of day at all 
subsequent visits.  The screening assessments/procedures have been organized into 4 distinct 
tiers (Table 6 and Figure 2).  All assessments/procedures in each tier should be completed, 
and 
eligibility 
to 
continue 
screening 
in 
the 
study 
confirmed, 
before 
any 
assessments/procedures from the next tier commence.  
Figure 2
Assessments to be Performed at Screening by Tier
CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia Rating, C-SSRS = Columbia 
Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire (also known as the 
Functional Activities Questionnaire), ISLT = International Shopping List Task (immediate and delayed recall), 
MMSE = Mini Mental State Examination, MRI = magnetic resonance imaging, PET = positron emission tomography, 
TB = tuberculosis.  
Cognitive assessments (Tier 1) are to be completed in the morning whenever possible, or consistently at the same time of 
day.  These assessments should be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) 
at Screening.  The investigator will determine whether the caregiver or informant must attend in person or whether 
telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other 
factors.
Volumetric MRI for PD assessment will be performed in all subjects immediately following the safety MRI assessments in 
the same imaging session (Tier 3).  
Amyloid PET imaging will be used to confirm all subjects have amyloid deposition in the brain (Tier 4).
Page 1564 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 46 of 139
9.1.1.2
Baseline Period
All Screening Visit assessments must be completed (and eligibility to progress confirmed) 
before any Baseline Visit assessments are performed.  The Baseline Visit assessments (per 
Table 6 and Section 9.5.1.2) are to be completed as soon as possible after completion of the 
final Screening Visit assessment (ie, PET scan) such that all Screening Visit and Baseline 
Visit assessments are completed within 50 days.
Inclusion and exclusion criteria will again be reviewed, vital signs including weight will be 
recorded, and a 12-lead ECG will be conducted in triplicate.  A routine physical examination 
will be conducted and a dermatological assessment and neurological examination will be 
performed.  A urine pregnancy test will be conducted for females of childbearing potential.  
Blood will be collected from all subjects for clinical chemistry and hematology, lymphocyte 
subset analyses, Ig analyses, and PD assessments.  Blood samples will be collected and 
stored for determination of a subject’s previous exposure to infective pathogens in the event 
of AEs that warrant further investigation occurring at a later point in the study.  Psychometric 
assessments will be administered to the subject in the order stated in Table 6.  The caregiver 
or informant needs to be present at this visit.  The Columbia Suicide Severity Rating Scale 
(C-SSRS) will also be administered (Section 9.5.1.5.11).
CSF will be obtained at this visit for PK and PD assessments (see Section 9.5.1.5.3).  
Blood will be collected from all subjects for pharmacogenomic (PGx) analyses of 
apolipoprotein E (ApoE4) and the NAT2 phenotype of subjects enrolled in the study (see 
Section 9.7.1.7.2).  
9.1.2
Randomization Phase
Subjects who complete the Baseline Visit assessments, and are eligible based on the 
inclusion and exclusion criteria (see Section 9.3.1 and Section 9.3.2), will begin the 
Randomization Phase within 7 to 10 days following completion of the Baseline Visit 
assessments.
The Randomization Phase will consist of a Treatment Period of 78 weeks duration and a 
Follow-Up Period of 12 weeks after the last dose of study drug.  
9.1.2.1
Treatment Period
Subjects will be randomized at the beginning of the Treatment Period and will receive study 
drug or placebo, to be administered orally QD with food.  Double-blinding to study drugs 
will be in effect throughout the Treatment Period.  The dose for a subject will not be changed 
during the study.  However, dose adjustment for Stage B may be considered and subjects 
already randomized to a dose that needs to be adjusted will be switched to continue their 
treatment at the new adjusted dose.
Safety withdrawal criteria for this study are detailed in Section 9.3.3.
Page 1565 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 47 of 139
Subjects will attend the study site every week for the first 4 weeks after beginning study 
drug, then fortnightly until 12 weeks have elapsed since first dose.  Visits will then be 
conducted at 16, 20, 26, 39, 52, 65, and 78 weeks after the first dose.  
9.1.2.2
Early Discontinuation
Subjects who discontinue taking study drug prematurely for any reason will undergo an 
Early Discontinuation (ED) Visit within 7 days of their last dose of study drug.  Follow-Up
Visits will also be scheduled 4 and 12 weeks after the last dose of study drug.  Subjects who 
discontinue study drug prematurely will also be scheduled to return to the study site to 
undertake limited efficacy assessments (MMSE, CDR, ADAS-cog14, CBB, and ISLT) at 
Week 53 (Visit 16) and Week 79 (Visit 18), if these 2 visits have not already been 
performed.
9.1.2.3
Follow up
All subjects, regardless of whether they complete all 18 months of treatment or discontinue 
study drug prematurely, will complete 2 posttreatment Follow-Up Visits; one 4 weeks after 
the last dose of study drug (Visit 19) and a second 12 weeks after the last dose of study drug
(Visit 20).  If clinically indicated, more frequent safety assessments can be conducted as part 
of unscheduled visits during the posttreatment Follow-Up period.
The end of the study will be defined as the date of the clinical database lock (ie, when all 
study data are collected and data validation is completed).  
As required by some regulatory agencies, the following estimates are provided: 

The study will begin in Nov 2014 and will end on or before Aug 2019.

The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Overview
The design of this study allows Proof of Concept to be established in subjects with 
MCI/Prodromal AD.  The study also allows investigation of efficacy in subjects with mild 
AD to determine whether the effects of E2609 in this later stage population are comparable 
with those established in the MCI/Prodromal population within this same study (see 
Section 9.2.3 for discussion of the Bayesian design used in this study).  
The inclusion criteria for the MCI/Prodromal cohort will be consistent with the NIA-AA 
criteria for MCI due to AD (Albert, et al., 2011) and will also meet the definition of 
Prodromal AD per Dubois et al., 2010 (see Section 9.2.2).  
Page 1566 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 48 of 139
There is no active or positive control for this study as at this time, there is no cure for AD, 
no known way of slowing the progression of this disease, and no approved treatment 
available to reverse the deterioration of AD.
The primary efficacy tool for this Proof of Concept study is the composite scale ADCOMS
(change from baseline in the derived ADCOMS at 18 months).  The ADCOMS 
(Hendrix, et al., 2012) represents a novel composite approach integrating components of well 
established tools (ADAS-cog, MMSE, and CDR) to improve sensitivity to disease 
progression and treatment effects in subjects with AD (see Section 9.2.4).
Secondary efficacy endpoints include a biomarker of neuronal degeneration (shrinkage of 
neurons), which is the change from baseline in total hippocampal atrophy at 12 and 
18 months of treatment in MCI/Prodromal subjects as measured by vMRI; an amyloid 
biomarker, which is the change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months 
of treatment in MCI/Prodromal subjects; and a cognitive and functional assessment, which is 
the change from baseline in the derived ADCOMS at 18 months of treatment in mild AD 
subjects.  Exploratory endpoints including assessments of efficacy, safety and other 
biomarkers are also included.
Randomization and stratification will be used in this study to avoid bias in the assignment of 
subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
Rationale for the selection of doses used in the study is provided in Section 9.4.4.  
9.2.2
Rationale for Study Population
By the time AD progresses to dementia, with loss of functional capabilities, the amyloid load 
in the brain has already reached a plateau and significant neurodegeneration has occurred 
(Jack, et al., 2010).  There is a growing consensus within the AD field that it may be 
necessary to initiate disease modifying treatments earlier, before the onset of clinical 
dementia (Aisen, et al., 2010).  It is possible that this consideration explains the failure of the 
humanized monoclonal antibody bapineuzumab (which targeted brain amyloid) to 
demonstrate clinical efficacy in late-phase studies in mild-to-moderate AD dementia.  
The primary patient population of focus in this study is subjects with MCI/Prodromal AD
and they will be recruited during both Stage A and Stage B of the study.  The mechanism of 
action of a BACE1 inhibitor where amyloid production is reduced means E2609 is more 
likely to be efficacious (ie, slow disease progression) the earlier in disease progression 
treatment is started, where limited neurodegeneration has occurred and associated clinical 
deficits are at a minimum.  Key safety aspects will be assessed in Stage A in which the 
MCI/Prodromal AD subjects have less advanced disease compared with subjects with mild 
AD who will also be recruited in Stage B.  
Page 1567 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 49 of 139
As discussed, efficacy is more likely to be observed in subjects with MCI/Prodromal AD but 
there is the possibility that efficacy will also be evident following administration of an
amyloid modifying agents such as E2609 in subjects with slightly more advanced disease 
such as mild AD.  A study of tarenflurbil, a selective Aβ(1-42)-lowering agent, on cognition 
and function in subjects with mild to moderate AD showed only the subjects with mild AD
had lower rates of decline than those in the placebo group in activities of daily living and 
global function; however, slowing of cognitive decline did not differ significantly 
(Wilcock, et al., 2008).  Similarly, differential effects on cognitive measures have been 
observed with solanezumab, where some benefit from treatment was observed in subjects 
with mild AD but not in subjects with moderate AD, although studies with solanezumab 
were considered to have failed to improve cognition or functional ability significantly 
(Doody, et al., 2014).  Therefore, it is relevant to compare the effect of the BACE1 inhibitor 
E2609 in 2 different subject populations that differ in terms of AD severity before the 
initiation of large Phase 3 clinical studies.
9.2.3
Rationale for the Use of Bayesian Adaptive Design
This study uses a Bayesian adaptive design for the MCI/Prodromal cohort only in Stage B.  
This design optimizes subject allocation and evaluation of efficacy in a smaller number of 
subjects by maximizing the number of subjects exposed to doses of interest.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to aid in making early stopping decisions.  Response adaptive randomization will be used to 
update the randomization probability among treatment groups at each interim analysis, such 
that subjects are more likely to receive a dose that is efficacious.  
Subjects with mild AD recruited in Stage B will be assessed as a “nested” population that 
does not follow the Bayesian adaptive design.  It was not considered appropriate to have a 
Bayesian design for both cohorts as this would have substantially increased the overall study
sample size, delayed analyses of dose response, and would have added background “noise”
for the comparison of subjects with MCI/Prodromal AD compared with those with mild AD. 
Data from each cohort will be analyzed independently for the purposes of decision making.  
A separate analysis of the 2 cohorts avoids the risk of data from subjects with mild AD 
confounding the results for the primary population (MCI/prodromal).  
9.2.4
Rationale for Clinical Endpoints
The ADCOMS (Hendrix, et al., 2012) was developed utilizing data from multiple studies to 
investigate responsiveness to progression and treatment effects rather than sensitivity to 
baseline deficits.  The score was built empirically with no a priori assumptions, using a 
partial least squares regression model for placebo data from 4 MCI studies with a duration 
>12 months.  A combination of cognitive and functional items was selected from a variety of 
well-established and validated scales that is most sensitive to change over time.  The partial 
least squares regression coefficients from the model were used to form a weighted composite 
score comprising a total of 12 individual items taken from the ADAS-cog (4 items), the 
MMSE (2 items), and CDR (6 items), that assess both cognition and global function.  
Performance of the ADCOMS has been assessed against the original scales in several studies.  
Page 1568 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 50 of 139
The use of the ADCOMS allows for substantial sample size reductions in non-enriched and 
enriched MCI populations even over a 12-month period by increasing sensitivity.  This 
derived score has shown adequate sensitivity in the MCI due to AD amyloid confirmed (CSF 
Aβ-positive) subgroup.  
The ADAS-Cog is the most widely used cognitive scale in AD clinical studies (Rosen, et al., 
1984). The 14-item version will be used in the present study since it is considered more 
sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects
(Fleisher, et al., 2007).
The MMSE is a cognitive instrument commonly used for screening purposes, for staging of 
disease severity and is often measured longitudinally in AD clinical studies to follow disease 
progression and treatment effects (Folstein, et al., 1975).
The CDR is a clinical global rating scale requiring the interviewing of both the subject and an 
informant who knows and has contact with the subject.  The CDR is a clinician-directed 
assessment of both cognition and function, and is intended to capture the state and therefore 
the disease stage of the individual.  The CDR has been proposed as an acceptable approach 
for following disease progression and confirming treatment in AD.
The FAQ collects information on 10 items concerned with performing daily tasks necessary 
for independent living. 
The FAQ is considered as a better indicator of clinical 
meaningfulness than cognitive change as it reflects the subject’s functional state and should 
correlate well with AD progression.  
The CBB is a brief, computer-administered cognitive test battery that requires approximately 
10 minutes for administration (Darby, et al., 2012; Fredrickson, et al., 2008; Maruff, et al., 
2009).  The CBB has been used to detect cognitive impairment in several neurodegenerative 
conditions including the measurement of cognitive function in healthy older adults and in 
adults with clinically diagnosed AD and prodromal AD (Darby, et al., 2009; Hammers, et al., 
2012; Lim, et al., 2012a; Lim, et al., 2012b). The administration, scoring, and reporting of 
the CBB is automated and highly standardized, resulting in cognitive paradigms that have 
been well-validated in neuropsychological and cognitive studies (Fredrickson, et al., 2008; 
Maruff, et al., 2009).  See Section 9.5.1.3.1 for further details.
The ISLT is sensitive to memory impairment that characterizes both AD and MCI (Lim, et 
al,. 2012a).  In MCI subjects, the magnitude of the impairment observed on the total recall 
and delayed recall trials on the ISLT was consistent with the magnitude of impairment 
expected to occur.  It is sensitive to the memory impairment that characterizes MCI with high 
amyloid (unpublished data from the Australian Imaging, Biomarker and Lifestyle Flagship 
Study of Ageing study).  Data are robust across different groups of healthy older individuals, 
and accordingly criteria used for defining abnormal performance are reliable (Thompson et 
al., 2011, Lim, et al., 2012a, Lim, et al., 2012b).  Data computations indicate that the ISLT 
will be sensitive to the expected changes in amyloid-related memory dysfunction with E2609 
treatment.
Volumetric magnetic resonance imaging is discussed in Section 9.2.5.4.
Page 1569 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 51 of 139
9.2.5
Rationale for Biomarkers
9.2.5.1
Overall Rationale
The biomarker strategy for this study includes the following aims:

To establish an amyloid load in the brain at study entry (via the PET eligibility inclusion 
criterion)

To evaluate safety (principally by magnetic resonance imaging [MRI])

To confirm a PD effect in terms of both Aβ in CSF and brain amyloid assessed by PET
and to establish that this PD effect is maintained long-term

To evaluate disease modification through longitudinal assessments of vMRI, amyloid 
PET, and CSF biomarkers of neurodegeneration (tau and p-tau)
These aims are discussed below in the context of the individual biomarker assessments to be 
used in this study.
9.2.5.2
Soluble Biomarkers in CSF
Aβ(1-x) captures the effect on the total Aβ component; therefore, the measurement of this Aβ 
isoform most appropriately represents the total pharmacologic effect of E2609 on Aβ(1-40)
+Aβ(1-42) and other C-terminally truncated Aβ peptides such as Aβ(1-38) through inhibition 
of BACE enzyme cleavage.  
Aβ(1-42) measurements in CSF have shown high correlation with results using [11C]PiB, 
suggesting that CSF Aβ(1-42) reflects fibrillar Aβ content (Grimmer, et al., 2009).  The 
aggregation of Aβ peptides into plaques, and subsequent retention of peptides in the brain 
parenchyma, accounts for reduced availability of Aβ to diffuse into the CSF.  The decreases 
in CSF Aβ concentrations that are seen in AD are believed to be related to this decrease in 
brain Aβ availability.
Both total tau (t-tau) and p-tau are sensitive markers of axonal and neuronal degeneration 
(t-tau) and neurofibrillary tangles (p-tau), and have been demonstrated to increase in parallel 
with disease progression (Chintamaneni and Bhaskar, 2012).  CSF tau measurements have 
been correlated with cerebral atrophy, while their ratios with Aβ42 have provided useful 
predictors of cognitive decline and progression to dementia due to AD.  Rebalancing 
dysregulated amyloid production early in the process may positively affect the 
neurodegenerative process and thus affect these markers and benefit the disease trajectory.  
Therefore, monitoring these markers in conjunction with amyloid imaging may provide 
further supportive evidence of efficacy.  
Baseline levels of Aβ(1-42), tau, and p-tau will also help elucidate the extent of AD 
pathology at entry to the study and can be combined with baseline levels of ApoE4
genotyping in addition to the baseline imaging variables to help explain differences in 
treatment response.
Page 1570 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 52 of 139
The study will be stratified at randomization for ApoE4 gene status in order to account for 
any ApoE status by treatment interaction or ApoE status by amyloid-related imaging 
abnormalities risk interaction.
9.2.5.3
Amyloid PET
Amyloid PET imaging will be performed in this study for 2 primary reasons: 1) to confirm 
the presence of AD pathology in the brain of subjects with MCI/Prodromal AD or mild AD
at entry to the study; and 2) to evaluate the effects of E2609 on amyloid levels in the brain, 
both by whole brain analysis (the average of 5 to 6 cortical regions) and brain region 
analysis.
Longitudinal amyloid PET imaging will be conducted after 18 months of treatment (or at ED, 
providing the subject has received at least 39 weeks of study drug) as an exploratory measure 
of the potential disease-modifying effects of E2609.  Longitudinal amyloid PET imaging will 
only be conducted until 18-month PET scans of acceptable quality have been obtained for at 
least 25 subjects per treatment arm for each amyloid PET ligand used.
9.2.5.4
vMRI
Volumetric imaging will be used to evaluate the effects of E2609 on rates of atrophy across 
the different dose groups and to provide support that effective treatment is associated with 
modification of disease course (secondary endpoint for the MCI/Prodromal population and 
exploratory endpoint for the Mild AD population).  A large body of data has shown that 
structural MRI reliably tracks disease progression in AD.  Atrophy tends to occur 
preferentially in the lateral temporal and posterior parietal regions during the early stages of 
disease and progresses towards the anterior regions of the brain (frontal cortex) in its later 
stages.  Clinically efficacious doses are predicted to be associated with a slowing in the rate 
of hippocampal atrophy compared with rates observed in the placebo and non-efficacious 
dose groups.  Treatment effects on left and right hippocampal, whole brain, and total 
ventricular volumes are exploratory endpoints.  
Annualized rates of change of 2% to 3% have been reported for the AD brain compared with
1% in MCI and <1% in age-matched controls (Hua, et al., 2010, Leung, et al., 2010).  
However, subjects with MCI due to AD-dementia (CSF Aβ <192 pg/ml or positive amyloid 
imaging) show rates of atrophy comparable to those observed in subjects with AD-dementia
(Hua, et al., 2009; Hua, et al., 2010; Leung, et al., 2010; Morra, et al., 2009), supporting the 
notion that such subjects are on similar trajectories as mild AD-dementia.  Lower levels of 
CSF Aβ42, amyloid positivity on PET imaging, and higher levels of CSF tau in addition to 
the presence of the ApoE4 allele have all been associated with greater rates of brain atrophy 
(Fjell, et al., 2010a; Fjell, et al., 2010b) and will be entered as covariates in various analyses.  
Hippocampal atrophy has also been shown to predict clinical progression independently of 
amyloid levels in the brain (Jack, et al., 2010), and this measure will be entered as a covariate 
in the analysis of the clinical endpoints along with the aforementioned variables.  
Page 1571 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 53 of 139
Brain volume (total ventricular volume, whole brain, temporal lobe) generally shows a 
modest correlation with performance on a number of cognitive scales (Hua, et al., 2009; Hua, 
et al., 2010; Freeborough, et al., 1997; Leung, et al., 2010).  Using volumetric analysis 
performed at 6-month intervals, these relationships and the effects of E2609 treatment will be 
explored further.  Recent advances in analysis software have made structural imaging more 
sensitive to detect small changes and able to reliably measure rates of atrophy at these 
intervals, particularly in the posterior parietal and the lateral temporal regions during the 
early stages of disease (Hua, et al., 2009; Hua, et al., 2010).  Given these observations, a 
demonstration of significant slowing or stabilization in the rate of atrophy in response to 
treatment, compared with placebo, will offer further support for disease modification.
9.2.6
Clinical Risks and Mitigation Strategy
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, and to mitigate clinical risk in the progression 
from 14 days of dosing in the MAD study to 18 months of treatment in this Phase 2 study.  
These safety aspects include the following:  

Two-stage study design:  there will be a pause in recruitment after 60 MCI/Prodromal 
subjects have been randomized to study drug (Stage A).  Only after the safety of E2609 
in these first 60 subjects (consisting of at least 12 weeks data for the latter subjects and 
longer dosing periods for the earlier subjects) has been reviewed by the DSMB and 
considered acceptable, will randomization of further subjects into the study commence 
(Stage B).

Immunology-related and infection-related exclusion criteria

Review of unblinded safety data by an independent DSMB at regular intervals

Safety withdrawal criteria based on CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 
(B cell) and other lymphocytes (absolute counts and percentage change from baseline), 
skin rash, reoccurrence of herpes virus infections including any oral herpes, genital 
herpes or shingles, other infections, MRI changes, ECGs, and pregnancy.
In addition to the features above, other safety aspects of this study designed to mitigate 
clinical risk include the following:  

Blinded safety data will be monitored by Eisai at regular intervals during the course of 
the study

Routine safety assessments will include the monitoring and recording of all AEs and 
SAEs, monitoring of hematology, blood chemistry, and urinalysis, measurement of vital 
signs, regular ECGs, physical and neurological examinations, and dermatological 
assessments at regular intervals.  Information for AEs relating to abuse potential will be 
collected via a detailed narrative.  Subjects reporting AEs relating to abnormal dreams or 
sleep-related events, or sleep terror will be questioned on the frequency and impact of 
these events.
Page 1572 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 54 of 139

As per the communication from the Food and Drug Administration (FDA) in Aug 2013, 
there are concerns that hypopigmentation of the skin and mucous membranes may occur 
with BACE1 inhibitory drugs.  Although no such effects have been seen with E2609 to 
date, assessments by a dermatologist will be performed at regular intervals during the
study.  These assessments will specifically include evaluation of any areas of 
depigmentation or any rash.  Dermatological assessments will be supplemented with a 
specific question to subjects regarding skin changes at each visit.  Any such changes 
could be referred to the dermatologist for further evaluation.  See Section 9.5.1.5.8 for 
further details.

Baseline and on-study blood, DNA, and CSF samples will be taken and stored for all 
subjects.  These samples may be tested in the event that a subject develops AEs that 
warrant further investigation (eg, if a subject develops a treatment-emergent infection) 
(see Section 9.5.1.2.3).

Central reading of safety brain MRI assessments (including any MRI evidence of 
demyelination) will be performed at Screening, at approximately 6-month intervals 
during the Treatment Phase of the study, and at the final Follow-Up Visit.

Full neurological examinations will be performed at Baseline and at regular intervals 
during the study by either a neurologist or a physician with comparable training and 
experience in undertaking neurological examinations.  Details of the neurological 
examination are given in Section 9.5.1.5.9.

Cognitive decline will be assessed as a safety assessment (ADAS-cog14, MMSE, and 
CBB).  Of particular importance will be the assessment of reaction time testing using the 
detection and identification tasks on the CBB.

An assessment of suicidality using the C-SSRS will be performed at Screening, Baseline,
and at regular intervals during the Treatment Phase and Follow-Up periods of the study
(see Section 9.5.1.5.11).

All subjects, regardless of whether they complete all 18 months of treatment or 
discontinue study drug prematurely, will have at least 2 off-treatment Follow-Up visits 
(4 and 12 weeks after the last dose of study drug).  More frequent safety assessments can 
be made as unscheduled assessments/visits during the off-treatment Follow-Up period, if 
clinically indicated.

An ophthalmic examination will be conducted at Baseline and if the subject experiences 
visual disturbances during the course of the study (see Section 9.5.1.2.1).
9.3
Selection of Study Population
Stage A will enroll 60 eligible MCI/Prodromal subjects at 25 centers in the United States.  
Stage B will enroll up to an additional 440 eligible MCI/Prodromal subjects at approximately 
125 centers globally; the final total number will depend upon whether the prespecified 
criteria for either early success or futility are met.  In addition, a separate cohort of 
approximately 200 mild AD subjects will be randomized and dosed during Stage B.
Page 1573 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 55 of 139
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (Albert, et al., 
2011) or AD dementia (McKhann, et al., 2011) and is "staged" or classified as either MCI 
(Stage A and Stage B) or mild dementia (Stage B only) and also complies with the 
following:  
Required at both Screening and Baseline:  
a.
Subjective Memory Complaint with evidence of concern about a decline in cognition 
from the subject, informant, or clinician’s observation
b.
Cognitive impairment of at least 1 SD from age adjusted norms in delayed recall on
the ISLT
c.
FAQ ≤20
d.
MMSE ≥20
2. Amyloid positive PET image based on centralized PET scan reading 
3. Males and females aged 50 to 85 years, inclusive at time of consent
4. Must have an identified caregiver or informant who is willing and able to provide 
follow-up information on the subject throughout the course of the study.  This person 
must, in the opinion of the investigator, spend sufficient time with the subject on a 
regular basis such that the caregiver or informant can reliably fulfill the study 
requirements and must provide separate written consent.  The caregiver or informant
need not be living in the same residence as the subject.  If the caregiver or informant is 
not residing with the subject, the investigator has to be satisfied that the subject can 
contact the caregiver or informant readily during the times when the caregiver or 
informant is not with the subject.  If in doubt about whether a subject's care arrangements 
are suitable for inclusion, the investigator should discuss this with the medical monitor.  
At visits where the CDR or FAQ are conducted, caregivers or informants need to either 
attend the visit in person along with the subject or be able to be contacted by telephone at 
the time of the visit.  The investigator will determine whether attendance in person is 
required or whether telephone contact will be suitable and will base this determination 
upon the functional ability of the subject among other factors.  
5. Subjects who are receiving acetylcholinesterase inhibitor (AChEIs) or memantine must 
be on a stable dose for at least 12 weeks before the Baseline cognitive assessments at 
Visit 2, with no plans for dose adjustment in the foreseeable future.  Treatment-naïve 
subjects can be entered into the study but there should be no plans to initiate treatment 
with AChEIs or memantine at the time of entry into the study.
Page 1574 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 56 of 139
6. Subjects must have been on stable doses of all other permitted chronically used
concomitant medications (ie, not related to their cognitive decline) for at least 4 weeks 
before randomization
7. Females must not be lactating or pregnant (as documented by a negative beta-human 
chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG or hCG) at Screening or 
Baseline.  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
8. Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days before study entry and must agree to use a highly effective method of 
contraception other than hormonal contraceptives (eg, total abstinence, an intrauterine 
device, a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) throughout the entire study period and for 30 days after study 
drug discontinuation.  If currently abstinent, the subject must agree to use a double barrier 
method as described above if she becomes sexually active during the study period or for 
30 days after study drug discontinuation.  Females who are using hormonal 
contraceptives must have been on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and must continue to use the same 
contraceptive during the study and for 30 days after study drug discontinuation.  All 
females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for ≥12 consecutive months, in the appropriate age group and without other 
known or suspected cause) or have been sterilized surgically (ie bilateral tubal ligation, 
total hysterectomy or bilateral oophorectomy, all with surgery ≥1 month before dosing).
9. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they 
and their female partners must meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 30 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 30 days after study drug discontinuation.
10. Provide written informed consent
11. Willing and able to comply with all aspects of the protocol
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:  
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD pathology, including any co-morbidities detected 
by neurological examination or MRI
2. Modified Hachinski Ischemic Scale >4 
3. History of transient ischemic attacks or stroke within 12 months of Screening
Page 1575 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 57 of 139
4. A history of epilepsy.  Subjects with a history of seizures (not including a history of 
simple febrile seizures in childhood) within 10 years of Screening.  Subjects with 
disturbance likely to be due to seizures within 5 years of Screening.  
5. Significant pathological findings on the brain MRI at Screening, including but not limited 
to:  more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter), 
any microhemorrhage which is symptomatic, a single macrohemorrhage greater than 
10 mm at greatest diameter, an area of superficial siderosis, evidence of vasogenic 
edema, greater than 3 lacunar infarcts or a single infarct >2 cubic centimeters involving a 
major vascular territory, evidence of severe microangiopathy, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformations, infective lesions or 
space-occupying lesions (eg, arachnoid cysts) or brain tumors (eg, meningioma).
6. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could confound the MCI/Prodromal or mild AD diagnosis or could 
interfere with study assessments or procedures 
7. A score of ≥8 on the 15-item Geriatric Depression Scale (GDS) at Screening
8. Abnormally low serum vitamin B12 levels for the testing laboratory (if subject is taking 
vitamin B12 injections, level should be at or above the LLN for the testing laboratory)
9. Thyroid stimulating hormone above the normal range.  Other tests of thyroid function 
with results outside the normal range should only be exclusionary if they are considered 
clinically significant by the investigator.  This applies to all subjects regardless of 
whether or not they are taking thyroid supplements.  
10. Any 
contraindications 
to 
MRI 
or 
PET 
scanning, 
including 
cardiac 
pacemaker/ defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices 
other than those approved as safe for use in MRI scanners).  Subjects who require 
sedation for MRI or PET scanning as per local guidelines need not be excluded.
11. Any contraindications to lumbar puncture (LP) for CSF sampling (eg, lower spinal 
malformation on physical examination, local spinal infection or other abnormality, 
including but not limited to obesity)
12. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately
13. History of Ig deficiency or other immunodeficiency disorders (including subjects known 
to be human immunodeficiency virus positive)
14. Subjects with chronic viral hepatitis
15. A history of tuberculosis (TB).  Subjects with no history of TB will be tested for previous 
TB exposure (eg, positive tuberculin skin test, interferon gamma release assay or other 
locally accepted tests) and a positive test will be exclusionary.
16. A history of ophthalmic shingles
17. A history of ocular herpes simplex virus (HSV) infection
18. Any live vaccine in the 3 months before randomization.  
19. Any active infection within the last 4 weeks prior to randomization.  For such cases, the 
timing of randomization can be extended (up to 4 weeks) to allow the infection to 
resolve; psychometric tests conducted at Visit 2 (eg, MMSE, CDR, etc) must be repeated.
Page 1576 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 58 of 139
20. Any chronic inflammatory disease that is not adequately controlled or that requires 
systemic or ocular immunosuppressive or immunomodulatory therapy.  Subjects with:  
a.
Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary 
disease where the condition is considered to be stable and adequately controlled by 
inhaled steroids need not be excluded.  
b.
Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on 
systemic immunosuppressive therapy need not be excluded.  
c.
Cutaneous manifestations of immunological disease that do not require systemic 
immunosuppressive therapy or systemic immunomodulatory therapy need not be 
excluded (topical steroid treatment is permitted).
21. CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below 
LLN and confirmed by a repeat test conducted 1 week after the initial test  
22. Ig (IgG, IgA, or IgM) levels below the LLN
23. Clinically significant deviation from normal in physical examination, vital signs, or 
clinically laboratory tests at Screening or Baseline
24. A prolonged QT/ corrected QT interval (QTc) interval (QTc >450 msec) at Screening or 
Baseline as demonstrated by average QTc interval from triplicate ECGs.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long 
QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval.  
25. Any other abnormality of the ECG at Screening or Baseline (including QRS >110 msec, 
abnormal electrical axis, PR interval >220 msec and conduction abnormalities) 
considered clinically significant by the investigator
26. Left bundle branch block at Screening or Baseline 
27. Persistent heart rate <50 or >100 beats per minute (bpm) at Screening or Baseline
28. Persistent systolic blood pressure (BP) >165 mmHg or <90 mmHg and diastolic BP 
>100 mmHg or <60 mmHg at Screening
29. History of cardiac arrhythmias.  Subjects with other heart diseases (eg, ischemic heart 
disease, clinically significant valvular heart disease) that are not stably and adequately 
controlled, or uncompensated heart failure (New York Heart Association Class III and 
Class IV)
30. Type 1 or Type 2 diabetes mellitus that is not well controlled
31. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer that did not require systemic 
therapy; these do not exclude the subject).  Subjects who had malignant neoplasms but 
who have had at least 5 years of documented evidence of no active disease before 
Screening need not be excluded.
32. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not 
stably controlled, or which, in the opinion of the investigator(s), could affect the subject’s 
safety or interfere with the study assessments
33. Hypopigmentation conditions (eg, albinism and vitiligo)
Page 1577 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 59 of 139
34. Known or suspected history of drug or alcohol dependency or abuse within 2 years before 
Screening, current use of recreational drugs or a positive urine drug test at Screening.  
Subjects who test positive for benzodiazepines or opioids in the urine drug screen need 
not be excluded if in the clinical opinion of the investigator, this is due to the subject 
taking prior/concomitant medications containing benzodiazepines or opioids for a 
medical condition that is not exclusionary and not due to drug abuse.
35. Has a “yes” answer to the C-SSRS suicidal ideation questions 4 or 5, or any suicidal 
behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit; or has been hospitalized or treated for suicidal behavior in the past 5 years before 
Screening
36. Violations of the medical restrictions as specified in the Concomitant Medications section 
of the protocol
37. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the principal investigator this operation does not interfere 
with study procedures and subject safety.
38. Participation in any other interventional clinical study related to cognitive impairment 
within 6 months before Screening unless it can be documented that the subject was in a 
placebo treatment arm
39. Currently enrolled in another clinical study or used any investigational drug or device 
within 60 days or 5 half-lives of the investigational medication (whichever is longer) 
preceding informed consent
40. Hypersensitivity to the study drug or any of the excipients or to other BACE inhibitors, or 
to the PET tracer, or components of its formulation
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED
Visit within 7 days of their last dose of study drug (see Section 9.1.2.2).  Follow-Up Visits 
will also be scheduled 4 and 12 weeks after the last dose of study drug (see Section 9.1.2.3).  
Subjects who discontinue study drug prematurely will also be scheduled to return to the study 
site to undertake limited efficacy assessments (MMSE, CDR, ADAS-cog14, CBB, and ISLT) 
at Week 53 (Visit 16) and Week 79 (Visit 18), if these 2 visits have not already been 
performed.
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition eCRF 
page.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Page 1578 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 60 of 139
Dosing eCRF page.  If a subject discontinues study drug and withdraws from the study at the 
same time, the ED Visit will be followed (see Section 9.5.5).
Safety-related withdrawal criteria for the study will include the following:  
a.
A withdrawal threshold will be set based on absolute counts of CD4 (T helper cells), CD8
(cytotoxic T cells), or CD19 (B cells).  The withdrawal threshold will be set at below the 
level of the LLN, at a level that represents a greater risk of opportunistic infection in the 
treated population.  For CD4 (T helper cells) the withdrawal threshold is 250 cells/µL.  
For CD8 (cytotoxic T cells) and CD19 (B cells) the withdrawal thresholds are 
150 cells/µL and 50 cells/µL, respectively.  Any subject who has CD4 (T helper cells), 
CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts below the withdrawal 
threshold as confirmed by a repeat test conducted within 1 week of the initial test will be 
withdrawn from the study.
b.
Subjects with CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute 
counts between the LLN and the withdrawal threshold will have lymphocyte subset
counts performed on a weekly basis.  Subjects with a >33% reduction from baseline in 
CD4 (T helper cells), CD8 (cytotoxic T cells), or CD19 (B cells) absolute counts will also 
have lymphocyte subset counts performed on a weekly basis.  For these subjects, the 
decision as to whether the subject remains in the study or is to be withdrawn from the 
study will be based upon clinical judgment and will take into account any clinical 
presentation in addition to the lymphocyte subset counts.  These subjects may continue 
with treatment if there is no clinical evidence of infection.  They will be discontinued 
from study drug if they have infections of a moderate to severe intensity (eg, subjects 
whose infections are not localized, or are systemically unwell, or who require systemic 
antiinfective drug treatment).
Table 1
Study Conduct Actions for Lymphocyte Subset Absolute Counts
Lymphocyte subset absolute counts
Action
Continue in or withdraw from 
study?
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below withdrawal 
threshold
Retest within 1 week
If retest performed within 1 week 
confirms lymphocyte subset
counts below the withdrawal 
threshold, subject to be withdrawn 
from study
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts between LLN and 
withdrawal threshold or >33% reduction from 
baseline in CD4 (T helper cells), CD8 (cytotoxic T 
cells), or CD19 (B cells) absolute counts
Lymphocyte subset counts to be 
performed weekly until counts 
return to ≥ LLN or no more 
than 33% reduction from 
baseline
Decision will be based upon 
lymphocyte subset counts and 
clinical judgment
LLN = lower limit of normal.
Page 1579 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 61 of 139
c.
Subjects with clinical evidence of infection will have their CD4 (T helper cells), CD8
(cytotoxic T cells), and CD19 (B cells) absolute counts measured.  Blood and other 
biological samples will also be collected for investigations of infective pathogens (eg, 
serological tests, quantitative polymerase chain reaction, microscopy, and culture) where 
appropriate.  In subjects with infection, if any of their absolute cell counts meets the 
withdrawal thresholds, study drug will be discontinued.  All subjects with severe 
infections will be withdrawn.  All subjects with herpes zoster (shingles) or ocular herpes 
infections will be withdrawn, regardless of severity of presentation.  Subjects with mild 
or moderate infection may continue treatment with study drug unless otherwise clinically 
indicated or otherwise specified below.  Specifically, when any of the CD4 (T helper 
cells), CD8 (cytotoxic T cells), and CD19 (B cells) absolute counts are between the LLN 
and the withdrawal thresholds or have shown >33% reduction from baseline, subjects 
with infections of moderate intensity will be discontinued from study drug (eg, subjects 
whose infections are not localized, or subjects who are systemically unwell, or who 
require systemic antiinfective drug treatment).  All subjects with infection who are 
withdrawn will be followed for a period of 12 weeks or until the infection resolves/
stabilizes or until the CD4 (T helper cells), CD8 (cytotoxic T cells), and CD19 (B cells) 
absolute counts have returned to >LLN (whichever comes latest).
Table 2
Study Conduct Actions for Lymphocyte Subset Absolute Counts 
and Infection
Criterion
Severity of Infection
Mild
Moderate
Severe
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts below 
withdrawal threshold
Withdraw
Withdraw
Withdraw
CD4 (T helper cells), CD8 (cytotoxic T cells), or 
CD19 (B cells) absolute counts between LLN 
and withdrawal threshold or >33% reduction 
from baseline in CD4 (T helper cells), CD8
(cytotoxic T cells), or CD19 (B cells) absolute
counts
May continue treatment 
with study drug unless 
clinically indicated
Withdraw
Withdraw
CD4 (T helper cells), CD8 (cytotoxic T cells), or
CD19 (B cells) absolute counts always >LLN 
and no reduction from baseline >33%
May continue treatment 
with study drug unless 
clinically indicated
May continue treatment 
with study drug unless 
clinically indicated 
(See (e) for exception)
Withdraw
LLN = lower limit of normal.
d.
A subject with any skin rash of moderate to severe intensity, or any rash lasting more 
than 72 hours regardless of severity (see (e) for exception), will be discontinued from 
study drug and a dermatological consult will be requested regardless of whether the rash 
is considered drug-related or due to other causes.  For cases where the investigator 
suspects a drug rash, regardless of severity, the subject will be discontinued from study 
drug, a dermatological consult will be requested, and a skin biopsy will be performed to 
confirm the diagnosis.  The skin rash will be treated as per standard care and will be 
followed up until resolution regardless of etiology or severity.
Page 1580 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 62 of 139
e.
Subjects who develop moderate to severe oral or genital herpes should be withdrawn 
from the study.  Subjects who develop a mild case of oral or genital herpes may remain in 
the study even if the event lasts more than 72 hours.
f.
Development of any
of the following features on MRI: 
vasogenic edema, 
macrohemorrhage, an area of superficial siderosis, or a symptomatic microhemorrhage.  
If discontinued from study drug, subjects will undergo an ED Visit within 7 days after 
discontinuation and will attend the Follow-Up Visits 4 and 12 weeks after the last dose of 
study drug.  They will also undertake an Unscheduled Visit (with MRI) at approximately 
4 weeks after the visit at which such MRI features were first identified.  An MRI will also 
be performed at approximately the time of the second Follow-Up Visit (Visit 20).  
Additional visits for safety may be arranged if clinically indicated in the opinion of the 
investigator, including after 12 weeks after the last dose of study drug.  At any time 
during the treatment period, subjects who have asymptomatic, treatment-emergent 
microhemorrhages found on MRI, but none of the features which merit discontinuation of 
treatment (ie, vasogenic edema, macrohemorrhage, an area of superficial siderosis, or a 
symptomatic treatment-emergent microhemorrhage) may continue with treatment.  These 
subjects will have safety assessments (including MRI) at approximately 4 weeks after the 
visit at which such MRI features were found.  They will also continue with the scheduled 
MRI scans.  Additional unscheduled MRI scans may be arranged on an individual subject 
basis in discussion with the study medical monitor.
g.
A postdose ECG with an average QTcF interval >500 msec from triplicate ECGs
h.
A postdose ECG with a QTcF interval increase from baseline >60 msec and a QTcF 
interval >450 msec as demonstrated from triplicate ECGs
i.
Any seizure (motor or non-motor)
j.
Pregnancy
9.4
Treatments
9.4.1
Treatments Administered
For this study the test drug is E2609 and the control drug is placebo.  All study drugs are to 
be administered orally, QD, with food.  As shown in Figure 1, there will be 4 treatment arms
in the MCI/Prodromal Cohort where E2609 will be administered at 3 doses (5 mg, 15 mg and 
50 mg) and the comparator is placebo.  In the Mild AD Cohort, there will be 3 treatment 
arms where E2609 will be administered at 2 doses, and the comparator is placebo.  The 
2 highest E2609 doses (15 mg and 50 mg) taken into Stage B, after the PK/PD and safety 
review from Stage A for the MCI/Prodromal group, will be used for the Mild AD population.
Study treatment will begin on Day 1 (at the study site) following Randomization and will 
continue for approximately 78 weeks.  Please refer to Table 7 and Section 9.5.1.4.1 for 
specific information on drug administration on days when PK sampling is to be performed.
Study drug doses will remain the same for each individual subject unless the interim PK/PD 
analysis determines that an entire dose level requires adjustment (Section 9.4.4). 
See 
Page 1581 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 63 of 139
Section 9.3.3 for safety related withdrawal criteria for the study.  If a subject develops a 
concurrent illness during the treatment period, the investigator should discuss with the 
medical monitor on whether dosing with study drug needs to be temporarily suspended.  As a 
general clinical guideline, dosing with study drug may be resumed after resolution or 
stabilization of the concurrent illness, after discussion with the medical monitor.  
9.4.2
Identity of Investigational Product
E2609 tablets of 5-mg, 10-mg and 25-mg dose strengths will be supplied.  Placebo tablets of 
identical appearance will also be available.  Each subject will receive 2 tablets, which 
combined will make up the required doses of E2609 5 mg, E2609 15 mg, E2609 50 mg, or 
placebo.  The tablets will be supplied by the Sponsor in labeled blister packs.  The product 
release certificates for E2609 and placebo will be included in the clinical study report for this 
protocol.
Subjects will be stratified and randomized, and drug will be dispensed, via an interactive 
voice and web response system (IxRS) system (see Section 9.4.3).
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study tablets will consist of either E2609 or placebo, or both (see Section 9.4.2.3 for 
labeling details).
9.4.2.1
Chemical Name, Structural Formula of E2609

Test drug code:  
E2609

Generic name:  
not applicable

Chemical name:  
International Union of Pure and Applied Chemistry

N-{3-[(4aS,5R,7aS)-2-Amino-5-methyl-4a,5-dihydro-4Hfuro[3,4-
d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-
5-(difluoromethyl)pyrazine-2-carboxamide

Molecular formula:  C19H18F3N5O2S

Relative molecular mass:  437.44  

Structural formula:  
Page 1582 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 64 of 139
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E2609 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.  The following information may be included but is not limited to:  

Protocol number

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier (ID)

Lot number/batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) is responsible for ensuring that the temperature 
is monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme.  The randomization scheme and identification for each subject will be included in 
the final clinical study report for this study.  The doses and number of treatment groups to be 
used for MCI/Prodromal subjects and for mild AD subjects are described in Section 9.4.1.
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor
will generate the randomized blister card identification numbers.  At enrollment, the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 3), the IxRS will assign each subject a unique randomization number.  
Page 1583 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 65 of 139
9.4.4
Selection of Doses in the Study
It is not known how the level of CSF or brain Aβ reduction is related to clinical efficacy.  
Therefore, in this study, doses will be selected such that at steady state, they will result in 
25%, 50%, and 75% reduction in CSF Aβ levels from baseline to cover a broad range of PD 
effects.
In Study 007, the relative bioavailability of a tablet formulation of E2609 in the fed and the 
fasted states compared with the capsule formulation in the fasted state (used in Studies 001 
and 002) was investigated.  It was found that when the tablet form of E2609 (50 mg) was 
administered with food, the exposure (ie, AUC) of the parent drug E2609 was higher, with 
lower maximum observed concentrations and reduced exposure to the metabolites, compared 
with either formulation in the fasted state.
Based on the PK/PD modeling using data from healthy volunteer Studies 001, 002, and 007, 
doses of 5 mg, 15 mg, and 50 mg QD administered as the tablet formulation with food in this 
study should achieve CSF Aβ reduction from baseline of approximately 25%, 50%, and 75% 
at steady state, respectively (Table 3).
Table 3
Predicted Steady State Plasma PK Parameters and CSF 
Amyloid β Reduction From Baseline
E2609 Tablet 
Daily Dose (mg) 
With Food
E2609 
Plasma Cmax,ss
(ng/ml)
E2609 
Plasma Css,av
(ng/ml)
E2609 Plasma
AUC(0-24h)ss
(ng.h/ml)
% Reduction 
CSF BACE1
Activity
% Reduction 
CSF A(1-x)
5
6.2
3.3
80.3
16.2
33
15
18.6
10
240.9
36.6
56
50
62.1
33.5
803.0
65.7
79
A(1-x) = amyloid beta monomer from amino acid 1 to x, AUC(0-24h)ss = area under the concentration x time curve at 
steady state from time zero to 24 hours, BACE1 = Beta-amyloid converting enzyme, CSF = cerebrospinal fluid,  Css,av = 
average steady-state concentration, Cmax,ss = maximum plasma concentration at steady state, PK = pharmacokinetics.
The PK/PD modeling described above, which was conducted using data obtained from
healthy volunteers, has also been supported by modeling of data from subjects with an 
underlying AD pathology (Study 101).  Furthermore, external data with another BACE1
inhibitor (MK-8931) showed a similar PD effect in AD patients as in healthy volunteers 
(Forman, et al., 2013).  Therefore we are confident that the modeling of E2609 effects in 
healthy subjects will be applicable for both MCI/Prodromal and Mild AD dementia patients.
The exposure of the highest dose in this study (50 mg QD tablet administered with food) is 
less than that of the 100 mg QD dose (capsule administered fasted) in Study 002.
The 100 mg QD dose administered for 14 days in Study 002 was well tolerated with 
no clinically significant changes in laboratory parameters, vital signs, or ECG parameters.  
On Day 15, for the 100 mg QD cohort in Study 002, there was a reduction of CD4 
Page 1584 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 66 of 139
lymphocyte counts compared with placebo (CD4 lymphocyte counts on E2609 decreased by 
3.1% from baseline, whereas the placebo control showed an increase of 8.7%), but this 
decrease was less than that observed at doses of 200 mg (22.9% decrease) or 400 mg (17.3% 
decrease).  No subjects had infections or drug rash while receiving E2609 100 mg QD or at 
lower doses in Study 002, whereas at 200 mg and 400 mg QD, 4 subjects had symptomatic 
orolabial HSV1 relapses and 2 subjects at the highest dose had drug rash.  The highest dose 
for Study 202 of 50 mg QD (tablet administered with food) is therefore expected to have a 
similar or better safety profile compared with the 100 mg QD capsule (administered fasted) 
in Study 002.  Specific exclusion criteria, blinded and unblinded safety monitoring 
procedures, and safety withdrawal criteria are included in this study in order to mitigate any 
immunology-related risk with E2609, particularly in light of the progression from 14 days of 
dosing (Study 002) to 18 months of dosing in this study.
Subjects in the MCI/Prodromal cohort, whether in Stage A or Stage B, will be randomized to 
receive either placebo or E2609 at 5 mg, 15 mg, or 50 mg QD.  Subjects with mild AD
(Stage B) will be randomized to receive either placebo or E2609 at 15 mg or 50 mg QD, but 
not the 5-mg QD dose.  The rationale for not including an E2609 5-mg QD dose in the dose 
regimens for subjects with mild AD is that more advanced disease may require greater 
reduction in CSF Aβ levels for comparable effects. 
After 60 MCI/Prodromal subjects in Stage A have completed 4 weeks of treatment, an 
interim analysis of the E2609 PK and PD profiles will be used to confirm the E2609 doses to 
be used for Stage B, where PD is measured as reductions from baseline in CSF Aβ(1-x) 
levels.  If the 95% confidence interval of the mean percentage change from baseline in CSF 
Aβ(1-x) measured after 4 weeks of treatment with a dose of E2609 does not include its 
intended target value (ie, 25%, 50%, and 75% reductions from baseline, respectively for 
E2609 at 5 mg, 15 mg, and 50 mg), PK/PD modeling will be conducted.  This PK/PD 
modeling will use the observed PK and PD data from Stage A and will relate the average 
steady state plasma concentration of E2609 to steady state CSF Aβ(1-x) percentage reduction 
from baseline after 4 weeks of dosing.  From this model, the new target plasma steady state 
concentrations of E2609 required to achieve the target levels of CSF Aβ(1-x) reduction will 
be estimated again.  Dose adjustment for Stage B may be considered if it is possible to get 
closer to the new target plasma steady state concentrations of E2609 required to achieve the 
intended target levels of CSF Aβ(1-x) reduction than is possible with the initially planned 
doses, given the limitation that E2609 dose adjustments will have to be in 5-mg increments 
or decrements.  Subjects already randomized to a dose that needs to be adjusted will be 
switched to the new adjusted dose and complete their treatment at this new dose.
If dose adjustment is required for Stage B, a protocol amendment reflecting the new doses 
will be submitted.  
9.4.5
Selection and Timing of Dose for Each Subject
E2609 is administered orally, QD, with food.  Study treatment will begin on Day 1 following 
randomization and will continue for approximately 78 weeks.
Page 1585 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 67 of 139
9.4.6
Blinding
E2609 and placebo will be administered as tablets of identical appearance.  
During the Randomization Phase and Follow-Up Phases, subjects and all personnel involved 
with the conduct and interpretation of the study, including investigators, site personnel, and 
Eisai staff will be blinded to the treatment codes (double-blind).  
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments (ie, those who are trained and certified to perform the various cognitive 
assessments that are undertaken in this study).  Furthermore, at the site, the notes and reports 
relating to safety assessments must be kept separate from the notes and reports relating to 
efficacy.
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety) 
until the time of unblinding, per the standard operating procedure.  
At the end of Stage A, PK and PD data will be provided to the sponsor by the PK and PD 
analysis laboratories using dummy subject numbers instead of actual subject numbers.  The 
same dummy subject number will be used for a subject’s PK and PD data.  These data will be 
used to evaluate whether E2609 exposure and PD effects are similar between MCI/Prodromal 
subjects in Stage A of the present study and healthy subjects in previous studies.  Thereafter, 
unblinded PK and PD data will only be provided to the sponsor after study completion.
In the event that emergency conditions require knowledge of the study treatment given, the 
blind may be broken via the code breaker facility within the IxRS.  Emergency procedures 
for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, 
the investigator should consult with the sponsor to ascertain the necessity of breaking the 
code.
At the conclusion of the study, all unused drug supplies are to be returned to the Eisai 
approved contract packaging vendor.
9.4.7
Prior and Concomitant Therapy
Medication (including over-the-counter medications) or therapy administered to the subject 
before the study (within 6 months of randomization) and during the study (starting at the date 
of informed consent) will be recorded on the Prior & Concomitant Medication eCRF or 
Non-Pharmacological Procedures eCRF.  The investigator will record on the Adverse Event
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition eCRF.  
Page 1586 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 68 of 139
Listings of prohibited and permitted drugs are provided in Appendix 2 (Prohibited 
medications are presented in Listing 1, Listing 2, Listing 3, Listing 4, and Listing 5.  
Medications that are permitted with restrictions are listed in Listing 6, Listing 7, and
Listing 8). 
The following agents are not permitted before randomization (specific timeframes are shown 
below) and throughout the study until after the last treatment visit:  

Anticoagulants (eg, warfarin, digabatrin) are not permitted for a period of 5 half-lives or 
7 days (whichever is longer) before randomization 

Drugs which may cause QTc prolongation are not permitted for a period of 5 half-lives or 
14 days (whichever is longer) before randomization 

Live vaccines are not permitted within 3 months before randomization.  This does not 
apply to non-live/inactivated vaccines

Ig therapy and biologic drugs are not permitted within 6 months before randomization

Systemic or ocular immunosuppressive or immunomodulatory drugs are not permitted for 
a period of 5 half-lives or 60 days (whichever is longer) before randomization
Subjects taking AChEIs or memantine must meet the following criteria in order to be 
included in the primary analyses: 

On a stable dose for 12 weeks before the Baseline cognitive assessments at Visit 2

Remain on a stable dose while on study
Subjects who initiate treatment with an AChEI or memantine during the study, or who 
change their dose of AChEI or memantine while on study, will be allowed to continue in the 
study, but their clinical efficacy data will be censored from the time of drug initiation for the 
primary analyses.
Subjects taking all other non-prohibited concomitant medications must meet the following 
requirements:  

Must be on stable dose for at least 4 weeks before randomization, except for medications 
that are administered as short courses of treatment or which are to be used intermittently 
as needed

Medications that are used as needed, rather than on a stable daily basis, and which are 
central nervous system (CNS) active and may affect cognitive function, are not permitted 
during a period of 72 hours before cognitive testing
Subjects who initiate treatment with or have dose adjustment of drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the investigator this will not interfere with study procedures or subject safety, and 
Page 1587 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 69 of 139
are not prohibited above.  If the subject initiates treatment for co-morbidities with a 
(non-prohibited) drug that may affect cognitive function, the subject should not have 
cognitive assessments performed until the dose has been stable for at least 4 weeks.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the Treatment Phase of 
the study.  CRAs will review treatment compliance during site visits and at the completion of 
the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license (required for United States sites) or 
medical registration number on the curriculum vitae

A signed and dated Clinical Trial Agreement (CTA)

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Page 1588 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 70 of 139
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, and (e) documentation of 
returns to the sponsor.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare Regulatory Agency).  As applicable, all unused study drugs 
and empty and partially empty containers from used study drugs are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and, together with unused study drugs that were shipped to the site 
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
Page 1589 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 71 of 139
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity, native language, handedness, 
and highest education level.
9.5.1.2
Baseline Assessments
Assessments to be made at Screening and Baseline and throughout the study are described in 
Section 9.5.1.3, Section 9.5.1.4, and Section 9.5.1.5.  
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history, current medications including AChEI and memantine use, and 
current medical conditions will be recorded at the Screening Visit.  All medical and surgical 
history within 10 years must be noted in the Medical History and Current Medical Conditions
eCRF.  Medical history will include history of cognitive impairment due to AD.  Subjects 
will be asked about history of TB, infections due to varicella zoster virus (chickenpox and 
herpes zoster/shingles) and HSV Types 1 and 2 (orolabial herpes/cold sores and genital 
herpes, respectively).  The medical history of such infections will include onset, duration, 
relapse frequency, severity, and treatments.  Subjects will also be asked about their 
vaccination history including vaccinations against varicella zoster virus and TB.  The 15-item 
GDS and modified Hachinski ischemic scale will also be assessed at Screening as part of the 
exclusion criteria.
Physical examinations (complete or routine) will be performed as designated in Table 6.  A 
complete physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, and skin, and a neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.  
An ophthalmic examination will be conducted at Baseline.  If the subject experiences visual 
disturbances during the course of the study, the subject will be referred to a specialist for a 
further ophthalmic examination including a retinal examination.
Additionally, at the Screening Visit, inclusion and exclusion criteria and prior medications 
will be reviewed with the subject and caregiver or informant, and a serum β-hCG pregnancy 
test (females of childbearing potential only) will be conducted.  Blood will also be collected 
for chemistry and hematology tests, thyroid function tests, lymphocyte subsets analysis, 
Page 1590 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 72 of 139
Ig levels, viral screening (for hepatitis B surface antigen and hepatitis C antibodies), 
vitamin B12, and a test for previous TB exposure.  Urine will be collected for urinalysis and 
drug screening.
Height will also be measured.
9.5.1.2.2
PSYCHOMETRIC ASSESSMENTS
The MMSE, CDR, FAQ, ISLT, and the CBB will be administered at Screening and Baseline 
to determine eligibility.  See Section 9.5.1.3.1 for further details. These assessments should 
be completed before more invasive assessments/procedures (eg, physical examination, ECG, 
blood draws).  
9.5.1.2.3
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Subjects will be encouraged to stay at the site after completion of LP for medical 
observation.  At Baseline, CSF will be collected by LP after fasting (preferred), or at least 
2 hours after the most recent meal.  The timing of the Baseline LP needs to be scheduled 
carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed 4 and 8 hours 
postdose and at a similar time of day (±1 hour) for each individual subject.  At visits where 
cognitive tests are also performed, the LP must be performed after the cognitive tests have 
been completed; the subjects should rest and drink some fluid to hydrate after the cognitive 
tests and before the LP.  The CSF sample will not be taken at the ED Visit if this visit occurs 
within 3 months of a previous CSF sample.  The CSF sample will be used for PD 
assessments including but not limited to CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE.  
Aβ(1-x) in both CSF and plasma will be measured using a commercially based 
enzyme-linked immunosorbent assay (ELISA).  The pre- and post-screening analysis of CSF 
Aβ(1-42), t-tau, and p tau will be performed using ELISAs.  BACE1 levels will be measured 
using internally developed fluorescence resonance energy transfer and ELISA based assay(s).  
Substrates of BACE1 inhibition may also be explored using Western blots or other amenable 
methodology if clinical observations warrant and if analytes can be reliably tested in samples 
collected.
The blood sample collected for PD analyses at Baseline should be collected shortly after 
completing the LP at Baseline.  The sample should be collected at fasting or at least 2 hours 
after the most recent meal.  
At the Baseline Visit, CSF and blood samples will be collected and stored for determination 
of prior exposure to any suspected infective agents in the event that the subject develops 
treatment-emergent AEs that warrant further investigation (eg, treatment-emergent infection).  
Testing may include, but not be limited to, serological tests (eg, HSV1 and 2), viral titer by 
quantitative polymerase chain reaction, or human leukocyte antigen genotyping.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the samples.
Page 1591 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 73 of 139
Amyloid PET
Screening amyloid PET data will serve as the baseline data (Table 6).  PET scanning will be 
performed with a locally approved Aβ imaging agent, eg, Amyvid.  Descriptions and detailed 
instructions for all imaging can be found in the imaging manual.
Pharmacogenetics
A blood sample will be obtained at Baseline and will be used to determine the ApoE
genotype (homozygous or heterozygous) and the NAT2 phenotype of subjects enrolled in this 
study.  The findings will be used in the statistical analysis to determine the effects on 
treatment response and safety.
The genomic DNA samples will be stored and may also be used to examine the role of 
genetic variability in subjects’ absorption, distribution, metabolism, and excretion, the 
development of AEs, or underlying AD.  Variations in E2609 exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlation of single–nucleotide 
polymorphisms with PK, safety, or PD data.
Details of PGx testing may be provided and reported separately.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
PSYCHOMETRIC ASSESSMENTS
The timing of psychometric assessments is shown in Table 6 and Table 7.  These assessments 
should be administered in the morning (or, if not possible, consistently at the same time of 
day) and should be completed before more invasive assessments or procedures (eg, physical 
examination, ECG, blood draws).  The order of assessments is: MMSE, CDR, FAQ, ISLT 
(immediate recall), CBB, and ISLT (delayed recall) at Screening; and MMSE, CDR, 
ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) at the Baseline 
Visit.
At visits where the CDR or FAQ are conducted, the investigator will determine whether the 
caregiver or informant must attend in person or whether telephone contact will be suitable, 
and will base this determination upon the functional ability of the subject among other 
factors.
The Derived Alzheimer’s Disease Composite Score: The primary efficacy endpoint is the 
change from baseline in the derived ADCOMS at 18 months of treatment in MCI/Prodromal 
subjects.
The ADCOMS is derived from the ADAS-cog (4 items), the MMSE (2 items), and the CDR 
(all 6 items), described below.  The ADCOMS is more sensitive to clinical progression 
compared with currently existing clinical batteries and requires smaller sample sizes for 
clinical studies in MCI/Prodromal AD or mild AD.  It also shows sensitivity to treatment 
Page 1592 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 74 of 139
effects with AChEIs.  The ADCOMS assesses both cognitive and functional domains and can 
be offered as a single primary clinical endpoint.  The ADCOMS has a range from 0 to 1.97.  
CogState Brief Battery: The CBB is a computer-based battery comprising 4 cognitive tests:  
1. Detection – a simple reaction time test where the subject presses a key when the card is 
turned face up from a pack of cards (“Has the card turned over”).  Speed of response is 
the measure.
2. Identification – a simple choice reaction time test where the subject presses 1 of 2 keys 
when the card just turned face up is either a red card or a black card (“Is the card red”).  
Speed of response is the measure.
3. One Card Back – a simple working memory test where the subject presses 1 of 2 keys 
when the card turned face up is either the card seen in the immediately previous trial or 
not (“Is the previous card the same”).  Accuracy of response is the measure.
4. One Card Learning – a visual learning and memory test where the subject presses 1 of 
2 keys depending on whether the card just turned face up has been seen before or not in 
the task (“Have you seen this card before in this task”).  Accuracy of response is the 
measure.
ISLT: The ISLT is a verbal learning and memory test assessing both immediate and delayed 
recall.  Subjects are read a list of 12 items that can be obtained at the local shopping center.  
Subjects are asked to recall as many of the items as possible and this immediate recall trial is 
repeated 3 times.  After a delay of approximately 15 minutes, in which time the CBB is 
performed, subjects are again asked to recall as many of the words on the shopping list as 
they can (ie, a delayed recall trial).  
Mini Mental State Examination: A 30-point scale that measures orientation to time and 
place, registration, immediate and delayed recall, attention, language, and drawing.  Scores 
range from 0 (most impaired) to 30 (no impairment).
Clinical Dementia Rating:
The CDR assesses 6 domains of subject function; memory, 
orientation, judgment and problem solving, community affairs, home and hobbies and 
personal care.  Each of these items has a maximum possible score of 3 points and the total 
score is a sum of the item scores (sum of boxes) giving a total possible score of 0 to 18 with 
higher scores indicating more impairment.
Alzheimer's Disease Assessment Scale - cognitive subscale: Discussed in Section 9.2.4.
Functional Assessment Questionnaire:
Either a caregiver or informant or the subject 
provides performance ratings (from 0 to 3) on 10 complex activities of daily living performed 
within the preceding 4 weeks.  Scores range from 0 (independent) to 30 (dependent).  
Page 1593 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 75 of 139
9.5.1.3.2
VOLUMETRIC MRI
Volumetric MRI will be used to evaluate disease modification as indicated by measurements 
of brain atrophy, including the change from Baseline in terms of the measured hippocampal 
volume based upon the centralized measurement of the structure on repeated MRIs.  A large 
number of studies, including the Alzheimer’s Disease Neuroimaging Initiative, have shown 
that quantitative measurements of hippocampal, whole brain, and total ventricular volume 
provide robust and reliable biomarkers of disease progression, and potential for assessment 
of PD efficacy.  
Volumetric MRI sequences will be collected for all subjects immediately following all safety 
MRI scans in the same imaging session.  Volumetric MRI will be conducted at either 1.5T or 
3T, and across multiple scanner types and the type of scanner used will be documented.  
Volumetric MRI analysis will be performed by a central imaging laboratory on MRI scans 
obtained at the times specified in Table 6 and Table 7, according to standard quality control 
and normalization procedures for measurements of the whole brain and total ventricular 
volume.  Measurements of the right and left hippocampal volumes will be based on a 
validated algorithm and conducted in the same laboratory.  Additional analysis of regions of 
interest and cortical thickness may also be performed.
Descriptions and detailed instructions for all imaging can be found in an imaging manual that 
will be provided to the study sites.
9.5.1.3.3
CEREBROSPINAL FLUID SAMPLING
CSF samples will be collected as specified in Table 6 and Table 7.  The CSF sample taken at 
the Baseline Visit will only be performed after confirmation of an amyloid positive PET 
scan.  See Section 9.5.1.2.3 for further details.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood and CSF samples will be collected for the determination of the concentrations of 
E2609.  Analyses of metabolite concentrations may be performed, depending on emerging 
data from other studies with E2609.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of analytes will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood samples will be collected as specified in Table 6 and Table 7.  Two PK samples will 
be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visits 5, 11, 14,
and 16, and 4 to 8 hours postdose at Visit 7 and Visit 18 (or at the ED Visit).  Therefore, 
Page 1594 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 76 of 139
subjects or their caregivers or informants must be instructed not to take their study drug at 
home on the day the PK sampling is performed.  Instead, subjects will take the study drug at 
the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or at the ED
Visit) the PK blood sample should be collected shortly after completing the LP.
Blood will also be drawn where possible at the first report of an SAE or severe unexpected 
AE and at its resolution.
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures for PK samples.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Biomarkers
Blood samples will be collected for PD assessments as specified in Table 6 and Table 7.  See 
Section 9.5.1.2.3 for further details.
For all subjects, baseline and on-study blood samples, DNA samples, and any collected CSF 
samples will be stored for up to 15 years.  
See the laboratory manual (to be supplied to study sites) for a description of the collection, 
handling, and shipping procedures of the biomarker samples.
Amyloid PET
An amyloid PET scan will be performed at Screening to confirm deposition of amyloid in the 
brain.  Longitudinal amyloid PET imaging will also be conducted after 18 months of 
treatment (or at ED, providing the subject has received at least 39 weeks of study drug).  
Longitudinal amyloid PET imaging will only be conducted until acceptable 18-month PET 
scans have been obtained for at least 25 subjects per treatment arm for each amyloid PET 
ligand used (Table 6).  PET scanning will be performed with a locally approved Aβ imaging 
agent, eg, Amyvid.
Amyloid PET imaging is an exploratory measure of the potential disease-modifying effects 
of E2609.  
Descriptions and detailed instructions for all imaging can be found in the imaging manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, lymphocyte subsets, Igs, and urine values; 
periodic measurement of vital signs and ECGs; performance of physical and neurological 
examinations; dermatological assessments; the C-SSRS; and safety MRIs as detailed in
Table 6 and Table 7.
Page 1595 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 77 of 139
Every effort should be made to keep the site staff responsible for reviewing laboratory 
reports and assessing AEs separate from the site staff responsible for the efficacy 
assessments (see Section 9.4.6).
9.5.1.5.1
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is E2609.  
The criteria for identifying AEs in this study are:  

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not
A laboratory result should be considered by the investigator to be an AE if it:  

Results in the discontinuation of study drug

Results in withholding of study drug pending some investigational outcome

Results in an intervention, based on medical evaluation (eg, potassium supplement for 
hypokalemia)

Results in any out-of-range laboratory value that in the investigator’s judgment fulfills 
the definitions of an AE with regard to the subject’s medical profile

Worsens (increases) to Grade 2 or higher based on the Sponsor’s Grading for Laboratory 
Values 
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit (Visit 20, as shown in Table 7).  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition eCRF.  SAEs will be collected for 12 weeks after the 
last dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
Page 1596 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 78 of 139
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Cognitive decline will be assessed as a safety assessment in addition to an efficacy 
assessment.  Cognitive assessments include the ADCOMS, ADAS-cog14, MMSE, and CBB 
(see Section 9.5.1.3.1).  If these assessments show cognitive decline during the Treatment 
Period, and if this cognitive decline is considered by the investigator to be excessive relative 
to the subject’s recent AD history, this finding should be reported as an AE.
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.11 for a description of the C-SSRS).  
All AEs must be followed for 12 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.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:  
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Page 1597 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 79 of 139
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:  

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:  
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An SAE is any untoward medical occurrence that at any dose:  

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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 
Page 1598 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 80 of 139
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error; any treatment-emergent significant laboratory abnormality; any seizures, 
ocular herpes, herpes zoster, or severe infection; any moderate to severe drug rash or any 
rash lasting more than 72 hours (regardless of severity); amyloid-related imaging 
abnormalities (vasogenic edema, macrohemorrhage, an area of superficial siderosis, or a new 
microhemorrhage); a “yes” answer to Type 4 or 5 suicidal ideation, or a “yes” response to 
any suicidal behavior on the C-SSRS.  These events of interest are to be captured using the 
SAE procedures but are to be considered as SAEs only if they meet one of the above criteria.  
All AEs associated with events of interest are to be reported on the eCRF whether or not they 
meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urinalysis, and 
CSF are summarized in Table 4.  Subjects should be in a seated or supine position during 
blood collection.  Table 6 and Table 7 show the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study.  
See Section 9.3.3 for safety withdrawal criteria related to absolute counts of CD4, CD8, and 
B lymphocytes, and for lymphocyte subset counts.
Page 1599 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 81 of 139
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell count, and white blood cell count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils)
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, phosphate, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma 
glutamyl transpeptidase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, total protein, triglycerides, 
uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, red 
blood cells, specific gravity, white blood cells
Other
Lymphocyte subset analyses (see Table 5).  Regulatory T cells will be measured using 
CD4, CD25, and CD127 cell surface markers and FoxP3 intracellular marker.  
Ig analyses (IgG, IgA, and IgM).
Viral screen (HCVAb [Hepatitis C] and HBsAg [Hepatitis B]).
Serum pregnancy test (females of child bearing potential only)
Tuberculosis Interferon Gamma Release Assays  
Tests for thyroid function and vitamin B12
Blood sample for storage for subsequent testing of immune status
Cerebrospinal fluid sampling
HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, Ig = immunoglobulin.
The 8 different surface markers (CD3, CD4, CD8, CD45, CD19, CD16, CD56, and CD14) 
will be measured in order to provide the lymphocyte subset data as shown in Table 5.  In 
addition, Regulatory T cells will be measured using CD4, CD25, and CD127 cell surface 
markers and FoxP3 intracellular marker.  
Table 5
Lymphocyte Subtyping 
Cell Type
Cell Surface Markers
T lymphocytes
CD3
T helper cells
CD3+, CD4
Cytotoxic T cells
CD3+, CD8
Mature B cells
CD3-, CD19
Natural killer cells
CD3-, CD16, CD56
Macrophages
CD14
Page 1600 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 82 of 139
Clinical laboratory tests during all phases of the study will be performed by a central 
laboratory.  All blood and urine samples will be collected and sent to the central laboratory 
on the day of collection unless otherwise instructed.  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the case report form [CRF] Completion Guidelines).  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5.2), the site 
must fax or email the SAE report including the laboratory report (as regionally required) to 
the sponsor using the SAE form (see Section 9.5.4.1).
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [bpm], respiratory 
rate [per minute], body temperature [in centigrade], and weight [kg]) will be obtained at the 
visits designated in Table 6 and Table 7 by a validated method.  Measurements of 
semi-supine BP and heart rate will be obtained.  All BP measurements should be performed 
on the same arm, preferably by the same person.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
A complete physical examination will be performed at Screening as described in 
Section 9.5.1.2.1.  At Baseline and during the Randomization Phase, routine physical 
examinations will take place as shown in Table 7.  These examinations will include the 
cardiovascular system, respiratory system, and neurological system.  Health status will be 
evaluated by brief evaluation of the eyes, ears, nose, throat, and other physical conditions of 
note.  The subject must be queried regarding changes in physical status since the last 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in Table 6 and Table 7.  Twelve-lead 
standard ECGs will be recorded in triplicate (1 minute apart) after subjects have been resting 
in the supine position for at least 5 minutes.
On any study day when ECG, vital signs, and blood samples are taken, these procedures 
should be conducted in the following order: ECG first, followed by vital signs, and then 
blood samples.
Page 1601 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 83 of 139
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see
Section 9.5.4.1).
9.5.1.5.7
SAFETY MRI
Safety brain MRI assessments will be performed at the times shown in Table 6 and Table 7.  
Additional safety MRI scans can be performed at unscheduled visits if clinically necessary.  
MRI acquisition and interpretation will be organized centrally to ensure reproducibility and 
consistency between units involved.
Safety MRIs will be acquired using a standardized procedure that will include
fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted 
sequences to determine the presence of focal lesions including, but not limited to, evidence 
for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous 
malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white 
matter abnormalities, and vasogenic edema.  The imaging sequence for the Screening/safety 
MRI will include: T2 weighted anatomic MRI to rule out major white matter changes, 
cerebral infarction or other structural lesions, and a high-resolution 3D T1-weighted scan 
with isotropic voxels with volumes of 1 mm3 or less.  In addition, both FLAIR for the 
detection of vasogenic edema and T2* Gradient Recall Echo for the detection of 
microhemorrhages will be acquired.  The 3D dataset will be reconstructed in transverse slices 
in Digital Imaging and Communications in Medicine format.  The results of this MRI 
assessment will also be used as the Baseline Period MRI, against which changes after drug 
administration will be compared.  Further details of the MRI protocol can be found in the 
Imaging Acquisition Guideline.  MRI acquisition and interpretation will be organized 
centrally to ensure reproducibility and consistency between units involved.
MRI imaging will be conducted on separate days from the scheduled visits.  MRI imaging 
should be conducted within the 7 days before Visits 14, 16, and 18 and at the second 
Follow-Up Visit (Visit 20).  In the event of an Unscheduled Visit, the investigator in 
consultation with the sponsor will determine whether or not a safety MRI should be 
conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed 
during the preceding 90 days.
At any time during the treatment period, subjects will be discontinued from study drug if they 
develop any of the following features on MRI: vasogenic edema, macrohemorrhage, an area 
of superficial siderosis, or a symptomatic microhemorrhage.  All of these features must be 
reported as study specific AEs (or AEs of special interest).  These subjects will undergo an 
ED Visit within 7 days after discontinuation and Follow-Up Visits at 4 weeks and 12 weeks 
after the last dose of treatment.  Subjects will also undertake an Unscheduled Visit (with 
MRI) at approximately 30 days after the visit at which such MRI features were first 
Page 1602 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 84 of 139
identified.  Additional visits may be arranged if clinically indicated in the opinion of the 
investigator, and may occur later than 12 weeks after the final dose of study drug.
9.5.1.5.8
DERMATOLOGICAL ASSESSMENT
Assessments by a dermatologist will be performed at the times shown in Table 6 and Table 7.  
These assessments will specifically include evaluation of any areas of depigmentation or any 
rash.  
In addition, subjects will be questioned by the investigator at each visit about any new lesions 
on the skin, orolabial area, genital area, mucous membranes and conjunctiva, or visually 
detectable changes that might represent a drug-induced rash/reaction or infection.  Subjects 
and their caregiver or informants will be instructed to contact the investigator promptly if 
they see any lesions or other symptoms that might be associated with a drug-induced rash or 
reaction, or infection, and the investigator will be required to review such AEs as soon as 
possible and consider an unscheduled physical and dermatological evaluation.  Detailed 
characteristics of any skin rashes will be captured in the eCRF.  Physical examination may be 
undertaken where indicated.  Treatment-emergent abnormal dermatological findings should 
be reported as AEs.
9.5.1.5.9
NEUROLOGICAL EXAMINATION
Neurological examinations will be performed at Baseline and at regular intervals during the 
study by either a neurologist or a physician with comparable training and experience in 
undertaking neurological examinations as shown in Table 6 and Table 7.  Details of these 
examinations will be captured in an eCRF.  The neurological examinations will monitor for 
new symptoms and signs which will then alert the investigator to consider new CNS 
pathology (especially slowly-evolving neurological conditions that may not lead to 
prominent symptoms).  Examples of neurological signs that may indicate new CNS 
pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition 
difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline in excess 
of expectations based on the subject’s recent history.  In such a situation, the investigator 
should consider (but not limited to) demyelination in the differential diagnoses, and should 
discuss with the sponsor’s medical monitor further investigations or treatment, which will be 
decided case by case.  Neurological examinations will also include the assessment of cranial 
nerve function, especially the olfactory nerve.  Treatment-emergent abnormal neurological 
findings should be reported as AEs.
9.5.1.5.10
PREGNANCY TEST
At Screening, females of childbearing potential will have a serum pregnancy test.  At 
Baseline and during the Treatment Phase, urine samples will be obtained from females of 
childbearing potential for pregnancy tests (see Table 7).
Page 1603 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 85 of 139
9.5.1.5.11
COLUMBIA SUICIDE SEVERITY RATING SCALE
An assessment of suicidal ideation and behavior using the C-SSRS will be performed at the 
designed time points in Table 6 and Table 7.  A “yes” answer to Type 4 or 5 suicidal ideation 
or a “yes” response to any suicidal behavior queries will trigger additional psychiatric 
evaluations by a psychiatrist to determine how the subject is to be managed clinically.  All 
sites are required to identify a psychiatrist for referral purposes.  The subject’s ability to 
continue to participate in the study will be determined by the investigator in consultation with 
the Medical Monitor. 
9.5.1.5.12
BIOMARKER SAMPLES
As noted in Section 9.5.1.2.3 and Section 9.5.1.4.2, CSF, blood, and DNA samples will be 
collected and may be tested in the event that a subject develops AEs that warrant further 
investigation.  
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 6 presents the schedule of procedures/assessments for the Prerandomization Phase.  
Screening assessments will be organized into 4 tiers (see below and Figure 2).
Table 7 presents the schedule of procedures/assessments for the Randomization Phase.
Page 1604 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 86 of 139
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
Phase
Prerandomization
Visit
Screening (Visit 1)
Baseline (Visit 2)
Procedures/ Assessments (to be completed in a maximum of 50 days)
Informed consent (subject and caregiver or informant)
X (Tier 1)
Demographics
X (Tier 1)
Medical historya
X (Tier 1)
Prior / concomitant medicationsb
X (Tier 1)
X
Vital signs including weightc 
X (Tier 1)
X
Height
X (Tier 1)
Complete physical examination
X (Tier 1)
Routine physical examination
X
CBB and ISLTd
X (Tier 1)
X
MMSEd
X (Tier 1)
X
CDRd
X (Tier 1)
X
FAQd
X (Tier 1)
X
ADAS-cog14d
X
15-item Geriatric Depression Scale
X (Tier 2)
Modified Hachinski ischemic scale
X (Tier 2)
C-SSRS
X (Tier 2)
X
12-lead ECGe
X (Tier 2)
X
Blood and urine for clinical laboratory testsf
X (Tier 2)
X
Blood for lymphocyte subset analysesg
X (Tier 2)
X
Blood for Ig analysesh
X (Tier 2)
X
Blood for viral screeni
X (Tier 2)
Blood for thyroid function testsj
X (Tier 2)
Test for previous TB exposure
X (Tier 2)
Urine drug screen
X (Tier 2)
Serum pregnancy test (females of childbearing potential only)
X (Tier 2)
Urine pregnancy test (females of childbearing potential only)
X
Safety and Volumetric MRIk
X (Tier 3)
Amyloid PET scanl
X (Tier 4)
Inclusion and Exclusion criteria
X (All tiers)
X
Adverse events
X (All tiers)
X
CSF sampling for PK, PD and storagem
X
Blood for PK assessmentsn
X
Blood for PD assessmentso
X
Blood sample for pharmacogenomics
X
Blood sample for storage for immune statusp
X
Dermatological assessmentq
X
Neurological examinationr
X
Ophthalmic assessment
X
AchEI = acetylcholinesterase inhibitor, AD = Alzheimer’s disease, ADAS-cog14 = Alzheimer’s Disease Assessment Scale 
- Cognitive subscale (14 items), CBB = CogState Brief Battery, CDR = Clinical Dementia Rating, CSF = cerebrospinal 
fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, FAQ = Functional Assessment 
Questionnaire (also known as the Functional Activities Questionnaire), HBsAg = hepatitis B surface antigen, 
HCVAb = hepatitis C virus antibody, HSV = herpes simplex virus, Ig = immunoglobulin, ISLT = International Shopping 
List Task (immediate and delayed recall), LP = lumbar puncture, MMSE = Mini Mental State Examination, 
MRI = magnetic resonance imaging,  PD = pharmacodynamics, PK = pharmacokinetics, PET = positron emission 
tomography, TB = tuberculosis.
Screening assessments/procedures have been organized into 4 distinct tiers.  All assessments and procedures in each tier 
should be completed (see Figure 2), and eligibility to continue confirmed, before any assessments/procedures from the 
next tier commence.  Similarly, all screening assessments and procedures must be completed, and eligibility to continue in 
the study confirmed, before any baseline assessments and procedures commence. Adverse events and eligibility against
inclusion and exclusion criteria must be assessed at each stage within the Screening Visit and at the Baseline Visit.  
Page 1605 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 87 of 139
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
All screening and baseline assessments are to be completed within 50 days.  The interval between availability of the 
results of the last screening assessment (PET scan) and the first baseline (Visit 2) assessments should be as short as 
possible and ideally should not exceed 7 days.  Visit 3 (Randomization) (see Table 7) should occur 7 to 10 days after 
completion of the Baseline visit (Visit 2) and confirmation of eligibility to continue in the study, unless additional time is 
required to take Exclusion Criterion #19 into account.  Thus, the total Prerandomization Phase may be up to 60 days.
a:
To include: mild cognitive impairment and AD history; history of TB, vaccination history against and infections due 
to varicella zoster virus (chickenpox and herpes zoster or shingles); infections due to HSV1 (orolabial herpes or cold 
sores) and 2 (genital herpes).  Medical history of infections to include: onset, duration, relapse frequency, severity,
and treatments.  
b:
Prior and concomitant medications include AChEIs and memantine, and other medications for cognitive decline.
c:
Weight, respiratory rate, body temperature, semi-supine blood pressure, and heart rate will be obtained.  
d:
To be completed in the morning whenever possible, or consistently at the same time of day.  These assessments 
should be completed before more invasive assessments/procedures (eg, physical examination, ECG, blood draws). 
The order of assessments is: MMSE, CDR, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) at 
Screening; and MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate recall), CBB, and ISLT (delayed recall) at the 
Baseline Visit.  At visits where the CDR or FAQ are conducted, the investigator will determine whether the caregiver 
or informant must attend in person or whether telephone contact will be suitable, and will base this determination 
upon the functional ability of the subject among other factors.
e:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
f:
Clinical laboratory tests include hematology, clinical chemistry and urinalysis, and include measurement of 
vitamin B12.
g:
Lymphocyte subsets to be measured include CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), 
CD16/CD56 (natural killer cells) and CD14 (macrophages).  Regulatory T cells will also be measured (CD4, CD25,
and CD127, FoxP3).  Viability staining may also be employed.
h:
Igs to be analyzed include IgG, IgA and IgM.
i:
Viral screen to include HCVAb (Hepatitis C) and HBsAg (Hepatitis B).
j:
Thyroid function tests include thyroid stimulating hormone, free triidothyronine and free thyroxine.
k:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion 
recovery, and diffusion-weighted imaging sequence images in addition to sequences for resting state functional MRI.  
MRI will be read by an approved central reader.  Volumetric MRI for PD assessment will be performed in all subjects 
immediately following the safety MRI assessments in the same imaging session.
l:
PET scanning will be performed with a locally approved -amyloid imaging agent, eg, Amyvid if available or an 
agent under clinical investigation if no agents are approved locally; the imaging agent must remain unchanged for an 
individual subject throughout the study. The PET image will be centrally read for the purpose of determining 
eligibility for inclusion into the study.
m:
CSF will be collected by LP after fasting (preferred), or at least 2 hours after the most recent meal.  Subjects will be 
encouraged to stay at the site after completion of LP for medical observation.  The timing of the Baseline LP needs to 
be scheduled carefully such that subsequent LPs (Visit 7 and Visit 18) can be performed at a similar time of day 
(±1 hour) for each individual subject. The LP must be performed after the cognitive tests have been performed; the 
subject should rest and drink some fluid to hydrate after the cognitive tests and before the LP.  The CSF sample will 
be used for PK and PD assessments.  A CSF sample will also be stored for testing in the event that the subject 
develops treatment-emergent adverse events that warrant further investigation (eg, treatment-emergent infection).
n:
The PK blood sample should be collected shortly after completing the LP.  The sample should be collected at fasting 
or at least 2 hours after the most recent meal.
o:
The PD blood sample should be collected shortly after completing the LP.  The sample should be collected at fasting 
or at least 2 hours after the most recent meal.
p:
A blood sample will be collected at Baseline and stored.  In the event that the subject develops treatment-emergent 
adverse events that warrant further investigation (eg, treatment-emergent infection), these samples may be tested to 
determine whether the subject already had prior exposure to any suspected infective agents.
q:
Assessments will be by a dermatologist.  These assessments will specifically include evaluation of any areas of 
depigmentation or any rash.  See Section 9.5.1.5.8 for further details.
Page 1606 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 88 of 139
Table 6
Schedule of Procedures/Assessments in Study 202: 
Prerandomization Phase (Visit 1 and Visit 2)
r:
To be performed by either a neurologist or a physician with comparable training and experience in undertaking 
neurological examinations.  Section 9.5.1.5.9 details what is included in the neurological examination.
Page 1607 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 89 of 139
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
EDd
19c
20c
UNS Visite
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
Routine physical examination
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Inclusion and Exclusion criteria
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Weight
X
X
X
X
X
X
X
X
X
Dermatological assessmentg
X
X
X
X
X
X
X
X
X
Neurological examinationh
X
X
X
X
X
X
X
Opthalmic examinationi
X
Concomitant medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
X
Xy
X
Clinical biochemistry and urinalysis
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Complete blood count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Blood for lymphocyte subset analysesl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Blood for Igsm
X
X
X
X
X
X
X
X
Xy
X
Urine pregnancy test (females of CBP only)
Xn
X
X
X
X
X
X
X
X
X
Blood sample for storage for immune statuso
X
X
X
X
X
X
X
Page 1608 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 90 of 139
Table 7
Schedule of Procedures/Assessments in Study 202: Randomization Phase (Visit 3 through Visit 20)
Phase
Randomization
Period
Treatment
Follow-Up
Visita
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17
18b
EDd
19c
20c
UNS Visite
Day
1
8
15
22
29
43
57
71
85
113
141
183
274
365
456
547
575
631
Week
1
2
3
4
5
7
9
11
13
17
21
27
40
53
66
79
83
91
Weeks elapsed since first dose
0
1
2
3
4
6
8
10
12
16
20
26
39
52
65
78
82
90
Nominal months elapsed since first dose
0
1
2
3
4
5
6
9
12
15
18
19
21
Procedures/ Assessments
CBB and ISLTp
X
X
X
X
X
X
X
X
X
MMSEp
X
X
X
X
X
X
X
X
X
CDRp
X
X
X
X
X
X
X
X
X
ADAS-cog14
p
X
X
X
X
X
X
X
X
X
FAQp
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
Xy
X
Safety and Volumetric MRIq
X
X
X
X
X
X
Amyloid PETr
X
X
Telephone contacts
X
X
X
X
X
X
X
X
Blood for PKt
X
X
X
X
X
X
X
X
Blood for PDu
X
X
X
X
X
X
X
X
X
CSF sampling for PK and PDv
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep/dream questionnairew
X
Randomization
X
Dispense study drugx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 1609 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 91 of 139
Notes for Table 7
ADAS-cog14 = Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items), CBB = CogState Brief Battery, CBP = childbearing potential, CDR = Clinical Dementia 
Rating scale, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, ED = Early Discontinuation, FAQ = Functional 
Assessment Questionnaire (also known as the Functional Activities Questionnaire), Ig = immunoglobulin, ISLT = International Shopping List Task, LP = lumbar puncture, MMSE 
= Mini Mental State Examination, MRI = magnetic resonance imaging,  PD = pharmacodynamics, PET = positron emission tomography, PK = pharmacokinetics, 
UNS = unscheduled.
a:
Visit 3 should be conducted 7 to 10 days after completion of the Baseline visit (Visit 2) assessments and confirmation of eligibility to continue in the study, unless additional 
time is required to take Exclusion Criterion #19 into account.  A window of ±3 days will be permitted for Visit 4 to 14 inclusive.  A window of ±10 days will be permitted for 
Visit 15 to 18 inclusive.  A window of ±3 days will be permitted for the Follow-Up Visits.  If use is made of the permitted visit windows, every effort should be made to bring 
the subject back in line with the “weeks elapsed since first dose” at subsequent visits.
b:
For subjects who discontinue taking study drug prematurely, the only assessments required at Week 53 (Visit 16) and Week 79 (Visit 18) are the MMSE, CDR, ADAS-cog14, 
CBB, and ISLT.
c:
All subjects, regardless of whether they complete all 18 months of treatment or discontinue study drug prematurely, will complete 2 posttreatment Follow-Up visits;
one 4 weeks after the last dose of study drug and a second 12 weeks after the last dose of study drug (Visit 19 and Visit 20 respectively).  If clinically indicated, more frequent 
safety assessments can be made as UNS assessments or visits during the posttreatment Follow-Up period. 
d:
Subjects who discontinue taking study drug prematurely for any reason will undergo an ED Visit within 7 days of their last dose of study drug.  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20, respectively).  Subjects will also be scheduled to return to the study site to undertake 
limited efficacy assessments (MMSE, CDR, ADAS-cog14, CBB, and ISLT) at Week 53 (Visit 16) and Week 79 (Visit 18) if they withdrew from study drug before these time 
points.
e:
Unscheduled visits may be conducted at any time that safety or safety MRI data indicate per protocol or as clinically indicated in the judgment of the investigator.  Note that 
not all assessments indicated under UNS Visits need be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit 
needs.
f:
Measurements of body temperature and semi-supine blood pressure and heart rate will be obtained.  
g:
Assessments will be by a dermatologist.  These assessments will specifically include evaluation of any areas of depigmentation or any rash.  Additional UNS dermatological 
assessments should be conducted in response to any dermatological AEs of concern, eg, depigmentation, rash, herpetic lesion.
h:
Examples of neurological signs that may indicate new central nervous system pathology that may need further investigation include (but not limited to) visual disturbance, 
dysarthria, dysphasia, muscle strength, limb weakness, hyperflexia, paraparesis, micturition difficulty or urgency or incontinence, ataxia, neuropsychiatric or cognitive decline 
in excess of expectations based on the subject’s recent history.  
i:
If the subject experiences visual disturbances during the course of the study, the subject will be referred to a specialist for a further ophthalmic examination including a retinal 
examination.
j:
Please refer to Section 9.4.7, which details prohibited and permitted medications in the study and associated timeframes.
k:
12-lead standard ECGs will be recorded in triplicate (1 minute apart).  
l:
Lymphocyte subsets to be measured include CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], CD16/CD56 [NK cells] and CD14 [macrophages]).  Regulatory 
T cells will also be measured (CD4, CD25 and CD127, FoxP3). Viability staining may also be employed.
m:
Igs to be analyzed include IgG, IgA, and IgM.
n:
An additional assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
Page 1610 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 92 of 139
o:
Blood samples will be collected and stored.  In the event that the subject develops treatment-emergent adverse events that warrant further investigation 
(eg, treatment-emergent infection), these samples may be tested to determine whether the subject already had prior exposure to any suspected infective agents.
p:
These assessments are to be completed in the morning whenever possible, or consistently at the same time of day.  These assessments should be completed before more 
invasive assessments or procedures (eg, physical examination, ECG, blood draws).  The order of assessments will be: MMSE, CDR, ADAS-cog14, FAQ, ISLT (immediate 
recall), CBB, and ISLT (delayed recall).  At visits where the CDR or FAQ are conducted, the investigator will determine whether the informant must attend in person or 
whether telephone contact will be suitable, and will base this determination upon the functional ability of the subject among other factors. 
q:
Safety MRIs will be acquired using a standardized procedure that will include gradient echo, long tau inversion recovery, and diffusion-weighted imaging sequence images in 
addition to sequences for resting state functional MRI.  MRI will be read by an approved central reader.  MRI imaging will be conducted on separate days from the scheduled 
visits.  MRI imaging should be conducted within the 7 days before Visits 14, 16, and 18 and 20.  In the event of an Unscheduled Visit, the investigator in consultation with the 
sponsor will determine whether or not a safety MRI should be conducted.  If an ED Visit takes place, an MRI is to be conducted if not already performed during the preceding 
90 days.  A volumetric MRI sequence will be collected in all subjects immediately following all safety MRI assessments.
r:
PET scanning will be performed with a locally approved amyloid imaging agent, eg, Amyvid, if available or an agent under clinical investigation if no agents are approved 
locally; the imaging agent must remain unchanged for an individual subject throughout the study.  A PET scan will only be performed at an ED Visit if the subject has been 
treated with study drug for at least 39 weeks.
s:
Site staff will contact the subject or the caregiver or informant the day before the PK blood sampling to provide instructions that subjects must not take their study drug at 
home on the day of the PK blood sampling.  During this telephone contact with the subject or the caregiver or informant, the site staff should document the time that the 
subject took their study drug that day, ie, the day before the PK blood sampling.
t:
Two PK samples will be obtained: one at predose (trough) and another 1 to 6 hours postdose at Visit 5, Visit 11, Visit 14 and Visit 16 and 4 to 8 hours postdose at Visit 7 and 
Visit 18 (or ED).  Therefore, subjects or their caregivers or informants must be instructed not to take their study drug at home on the day the PK sampling is performed.  
Instead, subjects will take the study drug at the clinic after collection of the predose PK sample.  At Visit 7 and Visit 18 (or ED) the PK blood sample should be collected 
shortly after completing the LP.
u:
PD blood samples should be collected at fasting or at least 2 hours after the most recent meal and, as far as is feasible, samples should be taken at the same time of day.  At 
Visit 7 and Visit 18 (or ED) the PD blood sample should be collected shortly after completing the LP.
v:
All visits at which CSF samples are scheduled to be taken also include blood PK and PD assessments and so the subject will be dosed at the clinic on these days. CSF will be 
collected by LP 4 and 8 hours postdose and at the same time of day as the subject's Baseline LP (±1 hour).  The CSF sample will be taken with the subject fasting (preferred) 
or at least 2 hours after the most recent meal.  The LP will be performed after the cognitive tests; the subject should rest and drink some fluid to hydrate after the cognitive 
tests and before the LP.  Subjects will be encouraged to stay at the site after completion of LP for medical observation.  The CSF sample will not be taken at the ED Visit if 
this visit occurs within 3 months of a previous CSF sample.
w:
Subjects reporting adverse events relating to abnormal dreams or sleep-related events, or sleep terror will be questioned on the frequency and impact of these events.
x:
The first dose of study drug will be given to the subject at the study site and the subject will be encouraged to stay at the site for an appropriate period of time for post-dose 
medical observation.
y:
Only if clinically significant abnormalities are found at Visit 19 and the investigator considers it necessary to repeat at Visit 20.  However, lymphocyte subsets and Igs should 
be repeated at Visit 20 if they were outside of the normal range (regardless of clinical significance) at Visit 19.
Page 1611 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 93 of 139
9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to Table 6 and Table 7 for the timings of the procedures and assessments to be 
performed during the study.  Screening assessments will be organized into 4 tiers (see 
Table 6, Section 9.1.1.1, and Figure 2).  See Section 9.5.1 for a full description of the 
procedures and assessments to be performed during this study.
Table 8 presents the number of blood and CSF samples, and the total volume of blood and 
CSF that will be collected throughout the study.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or if 
clinical symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood and CSF Sample Volumes
Assessment
Total number of 
collection time 
points
Sample volume, number of time 
points x volume per collection (mL)
Total 
volume 
(mL)
Screening and 
Baseline Periods
Treatment and 
Follow-Up
Periods
Blood
Chemistry
12
2 x 2 mL
10 x 2 mL
24 mL
Hematology
18
2 x 5 mL
16 x 5 mL
90 mL
Lymphocyte subset analyses
18
2 x 4 mL
16 x 4 mL
72 mL
IgA, IgM, IgG
9
2 x 2 mL
7 x 2 mL
18 mL
Thyroid function tests (thyroid 
stimulating hormone, free triidothyronine
and free thyroxine)
1
1 x 3 mL
None
3 mL
Viral screen (Hepatitis A and B)
1
1 x 4 mL
None
4 mL
Vitamin B12
1
1 x 2 mL
None
2 mL
Serum pregnancy test
1
1 x 2 mL
None
2 mL
Tuberculosis (interferon-gamma release 
assays) 
1
1 x 3 mL
None
3 mL
Blood for immune status
6
1 x 2 mL
5 x 2 mL
12 mL
PD sample
9
1 x 4 mL
8 x 4 mL
36 mL
PK analysis
7
1 x 2 mL
6 x 2 mL
14 mL
Pharmacogenetic sample
1
1 x 6 mL
None
6 mL
All blood samples, total volume collected
54 mL
232 mL
286 mL
CSF sampling
PD and PK samples
3
1 x 10 mL
2 x 10 mL
30 mL
CSF = cerebrospinal fluid, Ig = immunoglobulin, PD = pharmacodynamics, PK = pharmacokinetic.
Page 1612 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 94 of 139
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of AD.
Standard safety assessments incorporated into this protocol include vital signs, clinical 
laboratory assessments, physical examinations, ECG measurements, and reports of AEs.  
MRI will be used to detect vasogenic edema, macrohemorrhage, an area of superficial 
siderosis, or a symptomatic microhemorrhage and is a standard evaluation to ensure subject 
safety.  The C-SSRS has been endorsed by the FDA as a measure of potential suicidality 
(Guidance for Industry Suicidality).
A number of safety aspects have been built into the design of this study in light of the 
preclinical and clinical safety data with E2609, in addition to mitigating clinical risk in the 
progression from 14 days of dosing in the MAD study to 18 months of treatment in this 
Phase 2 study.  Details are provided in Section 9.2.6.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest
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 
when the investigator becomes aware of the event.
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 1 business day by emailing or faxing the 
completed SAE form.
SAEs, regardless of causality assessment, must be collected up to 3 months after the last dose 
of study or through the last visit, whichever is longer.  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.
Page 1613 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 95 of 139
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor, or its designee, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must discontinue study treatment.  
Page 1614 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 96 of 139
9.5.4.3
Reporting of Other Events of Interest
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.3.2
REPORTING OF SIGNIFICANT LABORATORY ABNORMALITY
Any significant treatment-emergent laboratory abnormality observed during the clinical 
study should be entered on the Adverse Event eCRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the laboratory 
abnormality does not meet serious criteria.  If the significant laboratory abnormality does not 
meet serious criteria, it must still be reported using the SAE form and in an expedited manner 
but should be noted as nonserious on the SAE form and the Adverse Event eCRF.
Page 1615 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 97 of 139
A laboratory result should be considered a treatment-emergent significant abnormality if the 
result:  

Is within normal limits at baseline and has increased in severity to meet the sponsor’s 
grading criteria for laboratory values of Grade 3 or above

Is outside normal limits at baseline and increases in severity to the sponsor’s grading 
criteria for laboratory values of Grade 4 or above

Is otherwise considered by the investigator to meet serious criteria as defined in
Section 9.5.1.5.2
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE or SAE.
9.5.4.3.3
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (as detailed in Section 9.5.1.5.2) should be entered on the Adverse 
Event eCRF and reported using the procedures detailed in Reporting of Serious Adverse 
Events (Section 9.5.4.1), even if the study-specific event does not meet serious criteria.  If the 
event does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the Adverse Event
eCRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
Page 1616 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 98 of 139
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be 
reported, as required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to withdraw from the study at any time for any reason.  All subjects who 
discontinue taking study drug prematurely for any reason will undergo an ED Visit within 
7 days of their last dose of study drug (see Section 9.1.2.2).  In addition, Follow-Up Visits 
will be scheduled 4 and 12 weeks after the last dose of study drug (Visit 19 and Visit 20,
respectively) (see Section 9.1.2.3).  See Table 7 for full details of the assessments to be 
performed at these visits.  Subjects who discontinue study drug prematurely will also be 
scheduled to return to the study site to undertake limited efficacy assessments (MMSE, CDR, 
ADAS-cog14, CBB, and ISLT) at Week 53 (Visit 16) and Week 79 (Visit 18), if these 2 visits 
have not already been performed.
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 withdraw prematurely from the study will be withdrawn for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal 
of consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary 
reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  Study 
disposition information will be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event eCRF.
Page 1617 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 99 of 139
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on 
Form FDA 1572 (where applicable) must sign the completed eCRF to attest to its accuracy, 
authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
Electronic source (eSource) methodology may be used for some of the clinical efficacy 
assessments performed in this study.
Page 1618 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 100 of 139
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
All statistical tests will be based on the 5% (2-sided) level of significance, except for the 
Bayesian methods on the primary endpoint.
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 statistical analysis plan, which will be finalized before
the first interim efficacy analysis.
9.7.1.1
Study Endpoints
See Section 9.2.3 for a discussion of the rationale for the selection and clinical relevance of 
the primary study endpoint.  Further information on the derived ADCOMS is described in 
Section 9.5.1.3.1 and information on the individual assessments that are included within the 
ADCOMS is described in Section 9.5.1.2.2.  
9.7.1.1.1
PRIMARY ENDPOINT

Change from baseline in the derived ADCOMS at 18 months of treatment in 
MCI/Prodromal subjects
9.7.1.1.2
SECONDARY ENDPOINTS
Change from baseline in:  

Total hippocampal atrophy at 12 and 18 months of treatment in MCI/Prodromal subjects 
as measured by vMRI

CSF Aβ(1-x) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects

The derived ADCOMS at 18 months of treatment in mild AD subjects
9.7.1.1.3
EXPLORATORY ENDPOINTS
Change from baseline in:  

The derived ADCOMS at 12 months of treatment in MCI/Prodromal and mild AD 
subjects

Total hippocampal volume at 12 and 18 months of treatment in mild AD subjects as 
measured by vMRI

CSF Aβ(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal subjects
Page 1619 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 101 of 139

CSF Aβ(1-x) and Aβ(1-42) after 4 weeks and 18 months of treatment in mild AD 
subjects

The following clinical assessments at 12 weeks and at 6, 9, 12, 15, 18, 19, and 
21 months:  ADAS-cog, CDR, MMSE, ISLT, CBB, and FAQ in MCI/Prodromal and 
mild AD subjects

CSF biomarkers of neurodegeneration (eg, tau and p-tau) at 18 months of treatment in 
MCI/Prodromal and mild AD subjects

Plasma and CSF amyloid, and CSF BACE1 measurements after 4 weeks and 18 months 
of treatment, and during posttreatment follow-up in MCI/Prodromal and mild AD 
subjects

Left and right hippocampal, whole brain, and total ventricular volume at 6, 12 and, 
18 months in MCI/Prodromal and mild AD subjects as measured by vMRI

Brain amyloid levels as measured by amyloid PET at 18 months in MCI/Prodromal and 
mild AD subjects

The population PK parameters of E2609 including the effect of intrinsic and extrinsic 
factors (including NAT2 phenotype) in MCI/Prodromal and mild AD subjects
9.7.1.2
Definitions of Analysis Sets

The Randomized Set is the group of subjects who are randomized to study drug.

The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug 
and have at least 1 postdose safety assessment.

The Full Analysis Set (FAS) is the group of randomized subjects who receive at least 
1 dose of study drug and have baseline and at least 1 postdose primary efficacy 
measurement.  

The Per Protocol (PP) Analysis Set is the subset of subjects in the FAS who sufficiently 
comply with the protocol.  The PP Analysis Set will be used to conduct a sensitivity 
analysis of the primary efficacy endpoint.  Details of the evaluability criteria will be 
determined before database lock and treatment unblinding, and will be specified in the 
statistical analysis plan.

The PK Analysis Set is the group of subjects with at least 1 quantifiable E2609 serum 
concentration accompanied by a documented dosing history.

The PD Analysis Set is the group of subjects who have a baseline PD measurement and at 
least 1 posttreatment PD measurement.
9.7.1.3
Subject Disposition
The number of subjects screened, the number (percent) of subjects who failed screening, and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition eCRF.  The distribution of the number of randomized subjects enrolled by each 
site will be summarized for each randomized treatment group.  The primary reasons for 
Page 1620 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 102 of 139
screen failures (did not meet inclusion or met exclusion criteria, AE, lost to follow-up, 
withdrawal of consent, and other) will be presented.
Study Completion: The number (percent) of randomized and treated subjects who completed 
the study and who withdrew from the study will be summarized according to the primary 
reason for discontinuation and secondary reason(s) for discontinuation, based on data 
reported on the Subject Disposition (Study Phase) CRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed the study, and withdrew from the study.  The primary reasons for discontinuation 
from the study are: AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, and other.  The secondary reasons for discontinuation from the 
study are: AE, subject choice, and other.
Completion of Study Treatment: The number (percent) of randomized and treated subjects 
who completed study drug and who discontinued from study drug will be summarized 
according to the primary reason for discontinuation and also according to secondary 
reason(s) for discontinuation, based on data reported on both the Subject Disposition 
(Study Phase) eCRF and ED from Study Drug eCRF.  The number (percent) will be 
presented by treatment group and total for subjects; randomized, not treated, treated, who 
completed study drug, and discontinued from study drug.  The primary reasons for 
discontinuation from the study drug are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, inadequate therapeutic response, and other.  
The secondary reasons for discontinuation from the study are: AE, subject choice, and other.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, MMSE and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, ApoE4 status (positive or negative), prior 
treatment with AChEIs or memantine (no or yes), and clinical subpopulation 
(MCI/Prodromal AD or mild AD).  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2014).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
WHO DD preferred term (PT).  Prior medications will be defined as medications that 
stopped before the first dose of study drug.  Concomitant medications will be defined as 
medications that (1) started before the first dose of study drug and were continuing at the 
time of the first dose of study drug, or (2) started on or after the date of the first dose of study 
drug up to the date of the last dose.  All medications will be presented in subject data listings.
Medications taken within the 12-week Follow-Up period will also be recorded.
Page 1621 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 103 of 139
9.7.1.6
Efficacy Analyses
MCI/Prodromal Cohort
The study in the MCI/Prodromal cohort is based on Bayesian adaptive design.  Frequent 
interim analyses will be performed to assess the probability of early success and futility and 
to make early stopping decisions.  Response adaptive randomization will be used to update 
the randomization probability among treatment groups at each interim analysis.  Key 
definitions relevant to the Bayesian aspects of the adaptive design are given below.
Study Definitions

Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect.  

ED90:
The lowest dose that achieves at least 90% of the dMax treatment effect in the 
derived ADCOMS.

Early Success:  The study in the MCI/Prodromal cohort will meet early success criteria 
if the probability that the ED90 at 18 months of treatment achieves 25% improvement 
over placebo is at least 80%.  Early success is achieved before all MCI/Prodromal
subjects complete 18 months of treatment and can only be determined after at least 
200 MCI/Prodromal subjects have been randomized.  If early success is declared before 
full randomization, the randomization of new MCI/Prodromal subjects will stop but 
subjects already randomized into the study will receive the full 18 months of treatment 
(following confirmation from the Sponsor’s Senior Management).  

Futility:  The study in the MCI/Prodromal cohort will meet statistical futility criteria if 
the probability that the ED90 is better than placebo by the clinically significant difference
of 25% is less than 5% at 18 months of treatment.  The statistical futility boundary is 
binding; if the statistical futility boundary is crossed the study will be considered to have 
failed.  

Study Success: The study in the MCI/Prodromal cohort will be considered a success if 
an ED90 at 18 months treatment has at least an 80% probability of achieving 25% 
improvement over placebo at either an interim analysis or at the final analysis.
The Mild AD Cohort
The analysis of the Mild AD cohort is based on the group sequential design.  Interim 
analyses in the Mild AD cohort will only be performed after the MCI/Prodromal cohort 
crosses the early success boundary.  The early efficacy signal based on the change from 
baseline of ADCOMS at 18 months is defined as crossing the interim-analysis boundaries for 
overwhelming efficacy in the mild AD population.  The O’Brien-Fleming (OF) boundaries 
based on Lan-DeMets alpha spending function will be used to assess overwhelming efficacy.  
The corresponding OF boundaries based on P values will be 0.076, 0.0221, and 0.0423 for 
the first, second, and final analyses, respectively, according to 2 planned interim analyses at 
the 60% and 80% information fraction.
Page 1622 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 104 of 139
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The primary analysis will be based on MCI/Prodromal subjects from the FAS with the 
prespecified censoring rule applied.  The primary endpoint is the change from baseline to 
18 months in the derived ADCOMS.  The dose-response of the primary endpoint is modelled 
with a first-order normal dynamic linear model, where Normal and Inverse-Gamma priors 
are used.  The primary efficacy analysis will calculate the Bayesian posterior probability that 
the dose identified is the most likely ED90 dose that achieves 25% improvement over the 
placebo arm.  At each interim analysis and the final analysis, 2 Bayesian probabilities will be 
summarized for each active dose: the probability it is the ED90 dose and the probability of 
achieving 25% improvement over the placebo arm.  
For the clinical efficacy data (ie, derived ADCOMS, MMSE, CDR, ADAS-cog, CBB, ISLT, 
and FAQ) subjects will be censored at the time of initiation of treatment with AChEIs or 
memantine, if they were not on these medications at the time of Baseline cognitive 
assessment (Visit 2), and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment with these medications at the time of 
Baseline cognitive assessment (Visit 2).  The value of the primary endpoint for censored 
subjects will be imputed using data up to the censoring time and Bayesian longitudinal 
modeling.
After unblinding, the primary endpoint will be analyzed using the Bayesian methods 
described above as well as conventional statistical methods.  The following additional 
Bayesian analyses will be conducted as sensitivity analyses:  

The primary endpoint will be analyzed regardless of initiation of treatment, or dose 
adjustment, with AChEIs or memantine using the same Bayesian analysis method as 
primary analysis.  This is an intent-to-treat analysis without any censoring.  

In case of early success, the primary analysis as well as the above sensitivity analyses 
will be repeated after all subjects have completed 18 months of treatment or have been 
lost to follow-up.
Statistical methods for the final conventional analyses will use a mixed-effects model with 
repeated measures (MMRM) on the change from baseline in the derived ADCOMS at 
18 months.  The model will include treatment groups, randomization stratification variables 
(the presence or absence of ongoing treatment with AChEIs or memantine or both, and 
ApoE4 status), and baseline ADCOMS as covariates.  These analyses will be performed on 
the FAS as well as the PP set.  In case of early success, the conventional analyses will also be 
performed using the data collected before the interim analysis.  
Page 1623 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 105 of 139
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The MCI/Prodromal Cohort
An MMRM will be used to analyze the following secondary endpoints:  

Change from baseline in total hippocampal atrophy at 12 and 18 months of treatment in 
MCI/Prodromal subjects as measured by vMRI

Change from baseline in CSF Aβ(1-x) after 4 weeks and 18 months of treatment in 
MCI/Prodromal subjects.  Data from early discontinuations will also be included.
Comparisons between each treatment group and placebo will be performed.
The Mild AD Cohort
The MMRM will be used to analyze the change from baseline of derived ADCOMS at 
18 months in mild AD.  If there is no treatment group-by-population interaction in the overall 
study, the MMRM analysis will include all subjects (MCI/Prodromal or mild AD) in the 
overall study.  Otherwise, the MMRM analysis will only include subjects in the mild AD 
cohort.  The comparison between placebo and active doses will be performed within mild 
AD subjects regardless of subjects included in the MMRM analysis.  Dunnett’s method will 
be used to control for multiplicity due to multiple comparisons.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
An MMRM will be used to analyze the following exploratory endpoints:  

Change from baseline in the derived ADCOMS at 12 months in MCI/Prodromal and mild 
AD subjects

Change from baseline in total hippocampal atrophy at 12 and 18 months in mild AD 
subjects as measured by vMRI

Change from baseline in CSF Aβ(1-42) after 4 weeks and 18 months in MCI/Prodromal 
subjects.  Data from early discontinuations will also be included. 

Change from baseline in CSF Aβ(1-x) and CSF Aβ(1-42) after 4 weeks and 18 months in 
mild AD subjects.  Data from early discontinuations will also be included. 

Change from baseline in the clinical assessments: ADAS-cog, CDR, MMSE, ISLT, CBB, 
and FAQ at 12 weeks and at 6, 9, 12, 15, 18, 19, and 21 months in MCI/Prodromal and 
mild AD subjects

Change from baseline in plasma and CSF amyloid and CSF BACE1 measurements after 
4 weeks and 18 months of treatment, and during posttreatment follow-up in 
MCI/Prodromal and mild AD subjects

Change from baseline in left and right hippocampal, whole brain, and total ventricular 
volume at 6, 12 and 18 months as measured by vMRI in MCI/Prodromal and mild AD 
subjects
Page 1624 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 106 of 139
A linear mixed-model will be used to analyze the following exploratory endpoints:  

Change from baseline in brain amyloid levels as measured by amyloid PET at 18 months 
in MCI/Prodromal and mild AD subjects

Change from baseline in CSF biomarkers of neurodegeneration (eg, tau, p-tau) at 
18 months of treatment in MCI/Prodromal and mild AD subjects
Data from early discontinuations will also be used as appropriate.  Comparisons between 
each treatment group and placebo will be performed. 
A linear mixed-model with repeated measures will be used to determine the relationship 
between the following endpoints:  

Change from baseline in the derived ADCOMS score and the change from baseline in 
biomarkers in CSF at 18 months in MCI/Prodromal and mild AD subjects

Change from baseline in the derived ADCOMS score and change from baseline in 
imaging biomarkers (hippocampal, whole brain, and total ventricular volumes) at 12 and 
18 months in MCI/Prodromal and mild AD subjects
ApoE status for heterozygous and homozygous E4 carriers will be included in the model to 
assess the effect of ApoE status in this relationship.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual E2609 concentration listings.  The PK 
Analysis Set will be used for summaries of E2609 concentrations. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, PGx, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate statistical analysis plan.  
Please also refer to Appendix 3.
Pharmacodynamic Analyses
The PD Analysis Set will be used for the summaries and analyses of PD biomarkers (CSF 
and plasma biomarkers, MRI endpoints).  CSF Aβ(1-x), Aβ(1-42), t-tau, p-tau, and BACE1
will be assessed and data will be presented graphically.  Baseline levels and changes in t-tau 
and p-tau will be correlated with changes in CSF Aβ(1-42), imaging markers, and ApoE4
status.
Summary statistics for CSF biomarkers will be assessed for evidence of a dose relationship.
Page 1625 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 107 of 139
Pharmacokinetic and Pharmacodynamic Analyses
The PK/PD relationship between CSF biomarker levels and exposure to E2609 in CSF will 
be explored graphically and any emergent relationship will be explored through population 
PK/PD modeling.  The PK/PD relationship between plasma PK parameters with other 
biomarkers may also be explored using similar methods.
Additionally, the relationship between plasma and CSF exposure to E2609 and the derived 
ADCOMS at 18 months, and the relationship between plasma and CSF exposure to E2609 
and the change from baseline for 18 months in the ADAS-cog, the CDR, and the MMSE,
will be explored graphically.  Any emergent relationship will be explored through population 
PK/PD modeling.
Exposure-safety analyses may also be conducted.
Pharmacogenomic Analyses
Blood samples will be used to determine the ApoE genotype and the NAT 2 phenotype of 
subjects enrolled in this study.  The genomic DNA samples may also be stored and used as 
described in Section 9.7.1.7.2.  Details of PGx testing may be provided and reported 
separately.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical and neurological examinations, and 
dermatological assessments), out-of-normal-range laboratory safety test variables, abnormal 
ECG findings, out-of-range vital signs, suicidality (C-SSRS), and results of the sleep 
questionnaire, along with the change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements will be summarized by treatment group using 
descriptive statistics.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to study drug will be summarized as cumulative extent of exposure in 
3-month intervals.  The number and percent of subjects will be presented by treatment group.  
Duration of exposure will be summarized using descriptive statistics in 3-month intervals.  
The number and percent of subjects will be presented by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17.0 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA PT and primary system organ 
class (SOC) are also captured in the database.
Page 1626 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 108 of 139
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 treatment group on the Safety Analysis Set.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once within an SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT.  The number (percentage) of 
subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe).  The number (percentage) of subjects with TEAEs will also be summarized by 
relationship to study drug (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 drug.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized by the following subgroups:  ApoE4 status (positive or 
negative), prior treatment with AChEIs or memantine (no or yes), and clinical subpopulation 
(MCI/Prodromal or mild AD).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  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 treatment group.  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 treatment group.  A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
Page 1627 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 109 of 139
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using International System of Units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 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.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
Lymphocyte subsets (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B cells], 
CD16/CD56 [natural killer cells] and CD14 [macrophages]) and regulatory T cells will be 
summarized in the same manner as other laboratory parameters.  Mean lymphocyte subsets
and the mean change from baseline in lymphocyte subsets will also be displayed graphically 
over time by dose.  
Serum IgG, IgM, and IgA will be measured and summarized in the same manner as other 
laboratory parameters.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
and treatment group.
Page 1628 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 110 of 139
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.  Shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to the end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:  
Absolute QTc interval prolongation:  

QTc interval >450 ms

QTc interval >480 ms

QTc interval >500 ms
Change from baseline in QTc interval:  

QTc interval increases from baseline >30 ms

QTc interval increases from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments.  
Cognitive assessments will include the ADAS-cog14, MMSE, CDR, and CBB (see 
Section 9.7.1.6).
9.7.2
Determination of Sample Size
9.7.2.1
Sample Size Rationale in the MCI/Prodromal Cohort
Primary endpoint – derived ADCOMS
The sample size and design characteristics to test the hypothesis for the primary objective 
based on the primary endpoint, change from baseline of the derived ADCOMS at 18 months, 
were determined by means of simulations.  Extensive study simulations have shown that a 
total of 500 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves 
a 25% improvement over placebo with a probability of at least 80% in the interim and final 
analyses.  There is at least a 90% probability of study success for the dose response scenarios 
where treatment was considered to have a clinically meaningful treatment effect.  
Simulations have also shown that if there is no obvious dose effect, the probability of falsely 
claiming superiority to placebo is at most 5%.  
Page 1629 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 111 of 139
For each of the 4 treatment groups (3 active doses and placebo) the final number of subjects 
per group will differ depending on the observed interim treatment responses.  The simulation 
plan will be an appendix to the statistical analysis plan and will present further details.
vMRI
The null hypothesis is that there is no difference between active dose and placebo.  There are 
3 null hypotheses corresponding to 3 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett’s
method with 1-sided alpha of 0.05.  The statistical power was estimated through simulation 
for a moderate dose-response assumption that the percent reduction in change from baseline 
of total hippocampal volume compared with placebo would be 15%, 20%, and 25% 
corresponding to the 3 doses, respectively.  The estimated power for the actual planned study 
sample size is 78% at 18 months assuming an attrition rate of 20% at 18 months.  Under a 
stronger dose-response assumption (ie, the percent reduction in change from baseline of total 
hippocampal volume compared with placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at 18 months.
Amyloid PET
The null and alternative hypotheses and the statistical test are the same as those for vMRI.  
To estimate the sample size for the amyloid PET imaging subgroup at 18 months, a common 
SD of the change from baseline was estimated at 0.33 and a reasonable mean difference 
between treatment and placebo was estimated as 0.25 (standardized uptake value ratio 
[SUVR]).  Assuming a moderate dose-response, the best dose would achieve a difference of 
0.25 (SUVR) and the middle and low doses would achieve a difference of 0.2 and 0.15 
(SUVR), respectively, this would require a total of 100 subjects from all 4 arms at 18 months 
to achieve 80% power.
9.7.2.2
Sample Size Rationale for the Mild AD Cohort
ADCOMS at Month 18
The null hypothesis is that there is no difference between active dose and placebo.  There are 
2 null hypotheses corresponding to 2 active doses.  The alternative hypothesis is that at least 
1 null hypothesis is false.  The null hypotheses will be tested using Dunnett’s test with 
2-sided alpha of 0.05 as described for the mild AD cohort in Section 9.7.1.6.2.  The statistical 
power was estimated through simulation for the dose-response assumption that the percent 
reduction in change from baseline of ADCOMS at 18 months compared with placebo would 
be 33% and 50% corresponding to the 2 doses, respectively.  The estimated power for the 
actual planned 200 mild AD subjects is at least 80% assuming a 2-sided alpha of 0.05.
Page 1630 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 112 of 139
9.7.3
Interim Analysis
The MCI/Prodromal Cohort
The Bayesian interim analyses and response adaptive randomization will be conducted by an 
unblinded external independent analysis group in accordance with the protocol.  Oversight of 
the Bayesian interim analyses and response adaptive randomization will be conducted by an 
independent unblinded committee that has expertise with Bayesian adaptive design in clinical 
studies to ensure that the response adaptive randomization process and interim analyses 
perform as expected.  The analysis group will provide the interim analysis outcomes to the 
committee at each interim analysis.  The committee will ensure the integrity of the interim 
analysis and response adaptive randomization process through review of efficacy data.  In 
addition, the committee will act in an independent advisory capacity to monitor the Bayesian 
interim analysis outcomes according to the early success and futility boundaries prespecified 
in the protocol.  The committee will not be charged with any subject safety issues; this will 
remain the responsibility of the DSMB.
If the predefined early success criteria are met during the recruitment period, further 
recruitment and enrollment of MCI/Prodromal subjects into the study will stop (following 
confirmation from the Sponsor’s Senior Management) and all currently randomized subjects 
will complete the full 18 months of treatment.  No further interim analyses will be conducted 
after achieving early success.  
If the predefined threshold for futility is reached, no additional subjects will be randomized 
into the study and the treatment of subjects already randomized into the study will stop and 
the study will be declared as “failed”.  All subjects will be monitored for safety for 3 months 
following their last dose.  
If neither early success nor futility is reached and the study reaches full randomization, all 
subjects will complete 18 months of treatment.  Interim efficacy analyses will be conducted 
every 3 months after full randomization is reached to assess futility and early success until all 
subjects complete 18 months of treatment.  After full randomization, all study subjects will 
stop treatment only in the event of futility.  
The DSMB will continue to monitor the safety aspects of the study throughout Stage A and 
Stage B.  Details will be provided in the DSMB Charter.  The study may be stopped for 
safety at any time.
An interim analysis will be conducted for safety when the first 60 MCI/Prodromal subjects 
have completed 12 weeks of treatment.  
The first Bayesian adaptive interim analysis will be conducted when 100 MCI/Prodromal 
subjects have been randomized into the study (ie, 60 subjects from Stage A of the study and 
the first 40 subjects from Stage B of the study).  Further interim efficacy analyses will be 
conducted after each additional 50 MCI/Prodromal subjects have been randomized, to a 
maximum of 500 MCI/Prodromal subjects (ie, at 100, 150, 200, 250, 300, 350, 400, 450, 
Page 1631 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 113 of 139
500 subjects randomized).  If the study reaches full randomization, additional interim 
analyses will be conducted every 3 months until all subjects complete 18 months of 
treatment.  The study will be monitored for futility at each interim analysis.  Starting at the 
interim analysis for 200 subjects, the study will be monitored for success at each interim 
analysis.  Each interim analysis will be conducted on data for the derived ADCOMS.
In addition, at each interim efficacy analysis, response adaptive randomization will be used 
to update the allocation of new subjects between placebo and active doses according to a 
predefined automated algorithm.
The Mild AD Cohort
A group sequential design will be used for the mild AD cohort.  This design includes 3 looks, 
2 interim looks (when 60% and 80% information fractions are achieved) and 1 final look.  
The information fraction is the number of assessments in all treatment arms divided by the 
total number of expected assessments.  Interim analyses will be performed after the 
MCI/Prodromal cohort crosses the early success boundary.  The corresponding efficacy 
boundaries will be 0.076, 0.022, and 0.0423 for the first, second, and final analyses, 
respectively.  If the actual information fraction during the interim analyses is different from 
60% or 80% at the interim, the efficacy boundaries will be adjusted based on the actual 
information fraction.  
If early success in the MCI/Prodromal cohort is not achieved before the final analysis that is 
performed when all subjects have completed 18 months treatment, then only a final analysis 
will be performed in mild AD subjects.  In the event of futility in the MCI/Prodromal cohort, 
an analysis will be performed for the mild AD cohort based on the data for mild AD subjects 
available at that time. 
Randomization into the Mild AD cohort will remain at a fixed schedule throughout Stage B 
of the study.  
The interim analyses in the Mild AD cohort will be conducted by an independent analysis 
group.
9.7.4
Other Statistical/Analytical Issues
Adaptive Randomization in the MCI/Prodromal Cohort
Randomization to placebo or 1 of 3 dose groups of E2609 will be fixed for the first 
100 subjects randomized in the study (1:1:1:1; placebo to each of the 3 active doses).  
Randomization probabilities to each treatment group will be updated at each interim analysis, 
such that the randomization probability will be increased for the placebo group and dosage 
groups that represent the potential target dose (ED90), and simultaneously decreased for other 
active arms. 
Page 1632 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 114 of 139
Within the 2 clinical populations (MCI/Prodromal and mild AD), subjects will be stratified at 
randomization by ApoE4 status (positive or negative) and prior treatment with AChEIs or 
memantine or both (yes or no).
Subjects with mild AD will be randomized to placebo or 1 of 2 dose groups of E2609.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the statistical analysis plan 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.
Page 1633 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 115 of 139
10 REFERENCE LIST
Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al.  Report of 
the task force on designing clinical trials in early (predementia) AD.  Neurology.  
2010;76(3):280–6.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.  The diagnosis 
of mild cognitive impairment due to Alzheimer’s disease:  Recommendations from the 
National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines 
for Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):270-9.
Chintamaneni M, Bhaskar M.  Biomarkers in Alzheimer’s disease: A Review.  ISRN 
Pharmacol.  2012 May 20;2012:984786.  
Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, et al.  BACE1
mRNA expression in Alzheimer’s disease postmortem brain tissue.  J Alzheimers Dis.  
2010;22(4):1111-22.
Darby D, Fredrickson J, Fredrickson A, Moore L, Sach J, Woodward M.  Community
screening for early signs of dementia.  Alzheimers Dement.  2009;5(5):3-4.  
Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, et al.  
Intraindividual cognitive decline using a brief computerized cognitive screening test.  
Alzheimers Dement.  2012;8(2):95-104.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of 
solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 
23;370(4):311-21. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. 
Revising the definition of Alzheimer's disease: 
a new lexicon. Lancet Neurol. 2010 
Nov;9(11):1118-27. 
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
Brain atrophy in healthy aging is related to CSF levels of Aβ1-42.  Cereb Cortex.  
2010;20(9):2069-79.
Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al.  
CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment 
and Alzheimer’s disease.  J Neurosci.  2010;30(6):2088–101.
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ.  Clinical predictors of 
progression to Alzheimer disease in amnestic mild cognitive impairment.  Neurology 
2007;68:1588-95.
Page 1634 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 116 of 139
Folstein MF, Folstein SE, McHugh PR.  “Mini-mental state.”  A practical method for grading 
the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12:189-98.
Forman MS.  The Novel BACE1 Inhibitor MK-8931 Dramatically Lowers CSF Beta-
Amyloid in Patients With Mild-to-Moderate Alzheimer's Disease.  Alzheimer’s Association 
International Conference, Boston, July 13-18, 2013.  Abstract O1-06-05.
Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P.  The use of effect sizes 
to characterize the nature of cognitive change in psychopharmacological studies: an example 
with scopolamine.  Hum Psychopharmacol.  2008;23(5):425-36.
Freeborough PA, Fox NC.  The boundary shift integral:  an accurate and robust measure of 
cerebral volume changes from registered repeat MRI.  IEEE Trans Med Imaging.  
1997;16(5):623–9.
Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, et al.  Βeta 
amyloid in Alzheimer’s disease:  increased deposition in brain is reflected in reduced 
concentration in cerebrospinal fluid.  Biol Psychiatry.  2009;65(11):927-34.
Guidance for Industry Suicidality:  Prospective Assessment of Occurrence in Clinical Trials.  
Draft guidance, September 2010, US Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research.
Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, et al.  Validity of a 
brief computerized cognitive screening test in dementia.  J Geriatr Psychiatry Neurol.  
2012;25(2):89-99.
Hendrix S, Logovinsky V, Perdomo C, Wang J, Satlin A.  A New Tool for Optimizing 
Responsiveness to Decline in Early AD. Oral presentation at the Clinical Trials on
Alzheimer's Disease Conference, October 29-31, 2012, Monte Carlo, Monaco.
Hua X, Lee S, Yanovsky I, Leow AD, Chou YY, Ho AJ, et al.  Optimizing power to track 
brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based 
morphometry:  an ADNI study of 515 subjects.  Neuroimage.  2009;48(4):668–81.  
Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, et al.  Mapping Alzheimer’s 
disease progression in 1309 MRI scans:  power estimates for different inter-scan intervals.  
Neuroimage.  2010;51(1):63-75.
Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al.  Brain 
beta-amyloid 
measures 
and 
magnetic 
resonance 
imaging 
atrophy 
both 
predict 
time-to-progression from mild cognitive impairment to Alzheimer’s disease.  Brain.  
2010;133(11):3336-48.
Page 1635 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 117 of 139
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. 
Introduction to the recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 2011 May;7(3):257-62. 
Leung KK, Clarkson MJ, Bartlett JW, Clegg S, Jack CR Jr, Weiner MW, et al.  Robust 
atrophy rate measurement in Alzheimer’s disease using multi-site serial MRI:  tissue-specific 
intensity normalization and parameter selection.  Neuroimage.  2010;50(2):516–23.
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, et al.  Use of the 
CogState Brief Battery in the assessment of Alzheimer’s disease related cognitive 
impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.  J Clin Exp 
Neuropsychol.  2012a;34(4):345-58.
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al.  Stronger effect of 
amyloid load than APOE genotype on cognitive decline in healthy older adults.  Neurology.  
2012b;79(16):1645-52.
Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, et al.  Cerebrospinal 
fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative 
preclinical analyses.  J Pharmacol Exp Ther.  2012;342(2):366-75.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al.  Validity of the CogState 
brief battery:  relationship to standardized tests and sensitivity to cognitive impairment in 
mild traumatic brain injury, schizophrenia, and AIDS dementia complex.  Arch Clin 
Neuropsychol.  2009;24(2):165-78.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al.  The 
diagnosis of dementia due to Alzheimer’s disease:  recommendations from the National 
Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease.  Alzheimers Dement.  2011;7(3):263-9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al.  Automated 3D 
mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's 
disease, mild cognitive impairment, and elderly controls.  Hum Brain Mapp.  
2009;30(9):2766-88.
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer’s disease.  Am J 
Psychiatry. 1984;141:1356-64.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al.  Toward defining 
the preclinical stages of Alzheimer’s disease:  recommendations from the National Institute 
on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease.  Alzheimers Dement.  2011;7(3):280-92.
Page 1636 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 118 of 139
Thompson TA, Wilson PH, Snyder PJ, Pietrzak RH, Darby D, Maruff P, et al.  Sensitivity 
and test-retest reliability of the international shopping list test in assessing verbal learning 
and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 2011 Aug;26(5):412-24. 
25.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy 
and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II 
trial. Lancet Neurol. 2008 Jun;7(6):483-93.
Page 1637 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 119 of 139
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 (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s or 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, and 
potential remote source document verification, will be conducted by the assigned CRA as 
described in the monitoring plan.  The investigator (or if regionally required, the head of the 
medical institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
Page 1638 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 120 of 139
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, computed tomography scans, MRIs, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.
Page 1639 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 121 of 139
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor).
Page 1640 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 122 of 139
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 CTA 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 CTA 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 CTA executed between the 
institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and
the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
Page 1641 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 123 of 139
12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
(conversion from 
g/dL0.6206)
Female (ULN=15.9 g/dL)
<11.1 – 10.0 g/dL
<111 – 100 g/L
<6.9 – 6.2 mmol/L
Male (ULN=17.7 g/dL)
<12.6 – 10.0 g/dL
<126 – 100 g/L
<7.8 – 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 white 
blood cell)
<3.40 – 3.0109/L
<3.40 103/uL – 3000/mm3
(ULN=10.80 103/µL)
<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 
< 0.70 103/uL – 800/mm3
<0.70 – 0.8109/L
(ULN=3.10 103/µL)
<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 
<1.40– 1.5109/L
<1.40 103/uL – 1500/mm3
(ULN=7.00 103/µL)
<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
<155 – 75.0109/L
<155 103/uL – 75,000/mm3
(ULN=379 103/µL)
<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) 
2 - 59 years (ULN=5.5 g/dL)
<3.5 – 3 g/dL
<35 – 30 g/L
59 -69 years (LLN-ULN)
3.6 g/dL – 4.8 g/dL
69 -79 years (LLN-ULN)
3.5g/dL – 4.8g/dL
79 -89 years (LLN-ULN)
3.5g/dL – 4.7g/dL
89 -150 years (LLN-ULN)
3.2g/dL – 4.6g/dL
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention 
indicated
Alkaline phosphatase 
Female:
18 -19 years
>101 – 3.0101
19 -61 years
ULN=107
61 -71 years
ULN=112
71 -150 years
ULN=108
Male
18 -19 years
>127 – 3.0127
19 -61 years
ULN=102
61 -71 years
ULN=103
71 -150 years
ULN=105
>3.0 – 5.0ULN
See previous column for 
ULN values
>5.0 – 20.0ULN
See previous column for 
ULN values
>20.0ULN
See previous column 
for ULN values
Alanine aminotransferase
Female:
>32 – 3.032
Male:
>44 – 3.0 x 44
Female:
>3.0 – 5.032
Male
>3.0 – 5.044
Female:
>5.0 – 20.032
Male:
>5.0 – 20.044
Female:
>20.032
Male:
>20.044
Aspartate aminotransferase >40 – 3.040
>3.0 – 5.040
>5.0 – 20.040
>20.040
Page 1642 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 124 of 139
Grade 1
Grade 2
Grade 3
Grade 4
Bilirubin 
(hyperbilirubinemia)
>1.2 – 1.51.2 
>1.5 – 3.01.2
>3.0 – 10.01.2 
>10.01.2
Calcium, serum-low 
(hypocalcemia) 
(conversion to mmol0.25)
<8.5 – 8.0 mg/dL
<2.13 – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>10.6 – 11.5 mg/dL
>2.65 – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
(conversion to mmol/L
0.02586)
0 -19 years
>169 – 300 mg/dL
>4.37 – 7.75 mmol/L 
19 -150 years
>199 – 300 mg/dL
>5.15 – 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
Female
>1.00 mg/dL – 1.51.00
Male
>1.27 mg/dL – 1.51.27
Female
>1.5 – 3.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>3.0 – 6.01.00
Male
>1.5 mg/dL – 3.01.27
Female
>6.01.00
Male
>1.5 mg/dL-3.01.27
Gamma glutamyl 
transpeptidase
Female
>60 IU/L – 3.060
Male
>65 IU/L – 3.065
Female
>3.0 – 5.060
Male
>3.0 – 5.065
Female
>5.0 – 20.060
Male
>5.0 – 20.065
Female
>20.060
Male
>20.065
Glucose, serum-high 
(hyperglycemia)
(conversion to mmol/L 
0.0555)
Fasting glucose value
>99 – 160 mg/dL
>5.5 – 8.9 mmol/L 
Fasting glucose value
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<65 – 55 mg/dL
<3.6 – 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) 
(conversion to mmol/L 
0.323)
<2.5 – 2.5 mg/dL
<0.81 – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
>5.5 – 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) 
<3.5 mEq/L – 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)
>144 mEq/L – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low 
(hyponatremia)
<134 mEq/L – 130 mmol/L
Not applicable
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high 
(hyperuricemia)
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
Not applicable
Female
>7.1 – 10 mg/dL 
Male
>8.6 – 10 mg/dL 
Both
≤0.59 mmol/L without 
physiologic consequences
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
LLN = lower limit of normal, ULN = upper limit of normal.
Page 1643 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 125 of 139
Appendix 2
List of Permitted and Prohibited Prior/Concomitant 
Medications
Prohibited medications are shown in Listing 1, Listing 2, Listing 3, Listing 4, and Listing 5.  
Medications permitted with restrictions are listed in Listing 6, Listing 7, and Listing 8.  
These may not be all-inclusive listings.  Please contact the medical monitor(s) if the 
investigators have any questions or concerns regarding any medication not listed that your 
subjects may be taking before enrollment or start during the course of the E2609-G000-202 
study.
Antibiotics, analgesics, and anti-inflammatory drugs intended for short courses of treatment 
are permitted and do not need to follow the restrictions of Listing 8 for a stable dose of 
4 weeks before Baseline.  If these medications may affect cognitive function but the 
medications are clinically indicated, then cognitive testing should not take place until at least 
72 hours after the last dose of the course of treatment.
Prohibited Prior/Concomitant Medications
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; names 
may be the ® or ™)
Comments
Prohibited from 14 days (or 5 half-lives, whichever is longer) before Baseline until after the last treatment visit
Anti-arrhythmic/ abnormal heart rhythm
Amiodarone
Cordarone; Pacerone
Incidence in females greater than males, Torsades de 
Pointes risk regarded as low
Disopyramide
Norpace
Incidence in females greater than males
Dofetillide
Tikosyn
Ibutilide
Corvert
Incidence in females greater than males
Procainamide
Pronestyl; Procan
Quinidine
Cardioquin; Quinaglute
Incidence in females greater than males
Sotalol
Betapace
Incidence in females greater than males
Antihistamine/ allergic rhinitis
Astemizole
Hismanal
No longer available in United States
Terfenadine
Seldane
No longer available in United States
Anti-anginal/ heart pain
Bepridil
Vascor
Incidence in females greater than males
Antibiotic/ bacterial infection
Clarithromycin
Blaxin
Moxifloxacin
Avelox
Sparfloxadin
Zagam
Page 1644 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 126 of 139
Listing 1
Drugs with High Risk of Torsades de Pointes or QTc Prolongation 
Generic name
Brand name (Names shown are not 
exhaustive and are examples only; names 
may be the ® or ™)
Comments
Listing 1 continued
Antimalarial/ malaria infection
Chloroquine
Aralen
Halofantrine
Halfan
Incidence in females greater than males
Antipsychotic/ anti-emetic/ schizophrenia/ nausea
Chloropromazine
Thorazine
Gastrointestinal stimulant/ heartburn
Cisapride
Propulsid
Antinausea/ nausea
Domperidone
Motillum
Not available in the United States
Sedative; antinausea/ anesthesia adjunct, nausea
Droperidol
Inapsine
Antibiotic; gastrointestinal stimulant/ bacterial infection; increase gastrointestinal motility
Erythromycin
Erythrocin; E.E.S.
Incidence in females greater than males
Antipsychotic/ schizophrenia
Haloperidol
Haldol
When given intravenously or at higher than 
recommended doses, risk of sudden death, QT 
prolongation, and torsades increases
Mesoridazine
Serentil
Thioridazine
Mellaril
Opiate agonist/ pain control, narcotic dependence
Levomethadyl
Orlaam
Methadone
Methadose; Dolophine
Incidence in females greater than males
Anti-infective/ pneumocystis pneumonia
Pentamidine
Pentam; NebuPent
Incidence in females greater than males
Antipsychotic/ Tourette’s tics
Pimozide
Orap
Incidence in females greater than males
Antilipemic/ hypercholesterolemia
Probucol
Lorelco
No longer available in United States
Anticancer
Arsenic trioxide
Trisenox
Used for leukemia
Vandetanib
Zactima
Used for thyroid cancer
Note: This list is not exhaustive.
QTc = Corrected QT interval.
Page 1645 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 127 of 139
Listing 2 Prohibited Medications Within 7 Days (or 5 Half-lives, Whichever is Longer) 
Before Baseline Until After the Last Treatment Visit)
Generic Name
Brand name (Names shown are not exhaustive and are examples only; 
names may be the ® or ™)
Anticoagulants
Warfarin
Coumadin, Jantoven
Dicumarol
Dicumarol
Dabigatran
Pradaxa
Enoxaparin
Lovenox
Dalteparin
Fragmin
Anisindione
Miradon
Danaparoid
Orgaran
Pentosan polysulfate sodium
Elmiron
Tinzaparin
Innohep
Adeporin
Normiflo
Heparin Sodium
Monoject
Bivalirudin
Angiomax
Argatroban
Argatroban
Lepirudin
Refludan
Fondaparinux 
Arixtra
Antithrombin III
ATryn, Thrombate III
Streptokinase
Streptase
Lanoteplase
Lanoplase
Reteplase
Retavase, Retevase
Staphylokinase
Eskinase, Heberkinasa Kabikinase, Streptase, Thrombosolv, Zykinase
Tenecteplase
TNKase
Urokinase
Abbokinase, Kinlytic
Alteplase, tPA
Activase, Cathflo Activase
Antiplatelet drugs
Aspirin and Plavix (only in subjects 
undertaking lumbar puncture in biomarker 
subgroup)
Aspirin or clopidogrel is permitted in all subjects.  Aspirin and clopidogrel 
in combination is permitted in subjects who are not to undergo lumbar 
puncture.
Note:  This list is not exhaustive.
Page 1646 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 128 of 139
Listing 3 Prohibited Medications Within 5 Half Lives or 60 Days, Whichever is 
Longer, Before Baseline Until After the Last Treatment Visit
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Systemic Immunosuppressantsa and Immunomodulatory therapy
Prednisolone
Deltasone, Prednicot, Prednisone Intensol, Rayos, Sterapred, Sterapred DS
Methylprednisolone
Medrol, Meprolone
Dexamethasone
Decadron, Dexasone, Diodex, Hexadrol, Maxidex
Azathioprine
Azasan, Imur
Mycophenolate
CellCept, Myfortic
Fingolimod
Gilenya
Methotrexate
Trexall
Ciclosporine
Gengraf, Neoral
Note:  This list is not exhaustive.
a:
Topical and inhaled formulations with minimal systemic exposure need not be prohibited.
Page 1647 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 129 of 139
Listing 4 Prohibited Medications Within 6 months before randomization
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Immunoglobulin therapy
Ranibizumab
Lucentis 
Bevacizumab
Avastin
Infliximab
Remicade
Etanercept
Enbrel
Adalimumab
Humira
Omalizumab
Xolair
Efalizumab
Raptiva
Immune globulin IV, 
IVIG, IGIV
Carimune, Flebogamma, Gamimune N, Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, Privigen, Sandoglobulin, Venoglobulin-S
Other monoclonal antibodies not listed here
Note:  This list is not exhaustive.
Page 1648 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 130 of 139
Listing 5 Prohibited Live Vaccines Within 3 Months Before Randomization Until After 
the Last Treatment Visit (this does not apply to non-live/inactivated vaccines)
Bacterial vaccines
Viral vaccines
Bacillus Calmette-Guérin vaccine against tuberculosis
Measles vaccination
Typhoid vaccination (oral)
Mumps vaccination
Cholera vaccination (oral)
Rubella vaccination
Oral polio vaccination (Sabin)
Yellow fever vaccination
Varicella (chickenpox) vaccination
Rotavirus vaccination
Japanese encephalitis vaccination
Live attenuated influenza vaccine (FluMist, Fluenz)
This list is not exhaustive 
Page 1649 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 131 of 139
Permitted Prior/Concomitant Medications
Listing 6
Medications Which Need To Be on a Stable Dose for 12 Weeks Before the 
Baseline Cognitive Assessments at Visit 2 and Remain on the Same Stable 
Dose from Baseline to Follow Up Visit 2
Generic name
Brand name (Names shown are not exhaustive and are examples only; 
names may be the ® or ™)
Cognitive Enhancers
Donepezil
Aricept
Rivastigmine
Exelon
Galantamine
Reminyl
Memantine
Nemanda
Note:  This list is not exhaustive.
Page 1650 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 132 of 139
Listing 7
Permitted medications used on PRN basis which are not to be used within 
72 hours before cognitive testing
Generic name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or 
™)
Opiates
Morphine
Astramorph PF, Avinza, Depo Dur, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph 
SR, RMS, Roxanol
Opiate Agonists
Meperidine
Demerol, Meperitab
Fentanyl
Actiq, Duragesic, Fentora, Onsolis, Sublimaze
Codeine
Codeine
Oxycodone
Dazidox, Endocodone, Eth-OxyDose, OxyContin, OxyFast, OxyIR, Percolone, Roxicodone, 
Roxicodone Intensol
Other opioids or opioid agonists which are used on PRN basis
Benzodiazepines and sedatives
Estazolam
ProSom
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Triazolam
Halcion
Midazolam
Versed
Lorazepam
Ativan
Flunitrazepam
Rohypnol
Temazepam
Restoril
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Chlordiazepoxide
H-Tran, Librium
Flurazepam
Dalmane
Zopiclone
(various)
Zolpidem
Ambien; others
Ramelteon
Rozerem
Amitriptyline
(various)
Dothiepin
(various)
Risperidone
Risperdal
Olanzapine
Zyprexa
Promethazine
Phenergan; others
Other benzodiazepines, tricyclic antidepressants, antipsychotics and other drugs which are used on PRN basis as sedatives
This list is not exhaustive 
PRN = Pro re nata
Page 1651 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 133 of 139
Listing 8
Permitted Medications
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or ™)
If to be used on a PRN basis see Listing 7.  If to be used chronically, subjects must be on a stable dose for ≥4 weeks before Baseline.  
Changes in dose or initiation of new concomitant medications for chronic use (not PRN use) is permitted but if the medication affects 
cognitive function, do not conduct cognitive testing until the dose is stable for 4 weeks.  
Antidepressants
Bupropion
Aplenzin, Budeprion, Buproban, Zyban, Wellbutrin
Nefazodone
Serzone
Rasagiline
Azilect
Selegiline
EMSAM
Isocarboxazid
Marplan
Phenelzine
Nardil
Tranylcypromine
Parnate
Citalopram
Celexa
Fluvoxamine
Luvox 
Escitalopram
Lexapro
Paroxetine
Paxil, Pexeva
Fluoxetine
Prozac, Sarafem, Selfemra
Sertraline 
Sertaraline, Zoloft
Duloxetine
Cymbalta
Venlafaxine hydrochloride
Effexor
Desvenlafaxine
Pristiq
Amitriptyline hydrochloride 
Elavil
Clomipramine hydrochloride 
Anafranil
Desipramine hydrochloride 
Norpramin
Doxepin hydrochloride 
Prudoxin, Silenor, Sinequan, Zonalon
Imipramine hydrochloride 
Tofranil
Nortriptyline hydrochloride 
Aventyl, Pamelor
Trimipramine maleate 
Surmontil
Protriptyline hydrochloride 
Vivactil
Amoxapine
Amoxapine
Trazodone hydrochloride 
Desyrel, Oleptro
Maprotiline hydrochloride
Ludiomil
Mirtazapine
Remeron Soltab 
Page 1652 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 134 of 139
Listing 8
Permitted Medications
Generic Name
Brand name (Names shown are not exhaustive and are examples only; names may be the ® or ™)
Mood Stabilizers (Listing 8 continued)
Carbamazepine 
Carbatrol, Epitol, Equetro, Tegretol, Tegretol XR 
Lamotrigine
Lamictal, Lamictal CD, Lamictal ODT, Lamictal XR
Valproic acid 
Depacon, Depakene, Depakote, Depakote ER, Divalproex Sodium, Stavzor, Valproate
Antipsychotics
Acetophenazine
Tindal
Aripiprazole
Abilify
Asenapine
Saphris
Olanzapine
Zyprexa
Chlorpromazine
Thorazine
Haloperidol
Haloperidol, Haldol
Clozapine
Clozaril, Fazaclo
Fluphenazine
Prolixin 
L-Methylfolate
Deplin, L-Methylfolate Calcium
Loxapine
Loxitane
Mesoridazine
Serentil
Perphenazine
Trilafon
Quetiapine
Seroquel
Risperidone
Risperdal
Thioridazine
Mellaril
Thiothixene
Navane
Trifluoperazine
Stelazine
Benzodiazepines
Estazolam
ProSom
Alprazolam
Alprazolam Intensol, Niravam, Xanax
Triazolam
Halcion
Midazolam
Versed
Lorazepam
Ativan 
Flunitrazepam
Rohypnol
Temazepam
Restoril
Clonazepam
Ceberclon, Klonopin
Diazepam
Diastat, Dizac, Valium
Chlordiazepoxide
H-Tran, Librium
Flurazepam
Dalmane
Zopiclone
Imovane, Zimovane
Zopidem
Ambien, Ambien CR, Intermezzo, Stilnox, Stilnoct, Sublinox, Hypnogen, Zolsana
Note:  This list is not exhaustive.
PRN = Pro re nata
Page 1653 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 135 of 139
Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for PD, PGx, and 
other biomarker analysis.  These samples may be used for discovery and validation to 
identify biomarkers that may be used for exploratory evaluation of response or safety-related 
outcomes as well as for use in diagnostic development.
The PGx samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study drug, and to explore the role of genetic variability 
in response.  Samples may be analyzed to determine a subject’s genotypes or sequence for a 
number of genes or non-coding regulatory regions.  The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug PK or 
therapeutic response.
Collection of the PD, PGx, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PGx,
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
Page 1654 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 136 of 139
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.  
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:  

CROs retained by the sponsor

IECs or IRBs that have responsibility for this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Page 1655 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 137 of 139
Given the research nature of the PD, PGx, and other biomarker analysis, it will not be 
possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, PD, PGx, or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments-certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and 
testing has been done in Clinical Laboratory Improvement Amendments-approved 
laboratories.
Page 1656 of 1658


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 138 of 139
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof of Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild Dementia Due to 
Alzheimer’s Disease
Investigational Product
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
SIGNATURES
Authors:
 Neuroscience and General Medicine Product
Creation Unit
Eisai Ltd.
Date
 Neuroscience and General Medicine
Product Creation Unit
Eisai Ltd. 
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Page 1657 of 1658
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
E2609-G000-202
Eisai
FINAL: 15 July 2014
Confidential
Page 139 of 139
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2609-G000-202
Study Protocol Title:
A 
Placebo-Controlled, 
Double-Blind, 
Parallel-Group, 
Randomized, Proof of Concept, Dose-Finding Study To 
Evaluate Safety, Tolerability and Efficacy of E2609 in Subjects 
With Mild Cognitive Impairment due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild Dementia Due to 
Alzheimer’s Disease
Investigational Product 
Name:
E2609
IND Number:
109308
EudraCT Number:
2014-002723-94
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
Page 1658 of 1658

SAP_001.pdf: 
Synoptic Clinical Study Report 
E2609-G000-202 
 
16.1.9 
Documentation of Statistical Methods 
The final approved Statistical Analysis Plan for this study is provided in the following pages. 
• Statistical Analysis Plan v1.0, 18 Feb 2020 
Page 1 of 26
Eisai
Confidential


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2609-G000-202 Amendment 08 
Study Protocol 
Title: 
A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, 
Dose-Finding Study To Evaluate the Safety and Tolerability of E2609 in 
Subjects With Mild Cognitive Impairment Due to Alzheimer’s Disease 
(Prodromal Alzheimer’s Disease) and Mild to Moderate Dementia Due to 
Alzheimer’s Disease 
Date: 
18Feb2020 
 
Version: 
Final Version 1.0 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 1 of 25 
 
Page 2 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
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 Objective(s) ......................................................................................6 
3.1.2 
Secondary Objective(s) ..................................................................................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 
Primary Endpoints .........................................................................................7 
5.1.2 
Secondary Endpoints .....................................................................................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 ........................................................................................9 
5.2.4 
Demographic and Other Baseline Characteristics .........................................9 
5.2.5 
Prior and Concomitant Therapy .....................................................................9 
5.2.6 
Treatment Compliance ...................................................................................9 
5.3 
Data Analysis General Considerations ..................................................................10 
5.3.1 
Pooling of Centers........................................................................................10 
5.3.2 
Adjustments for Covariates..........................................................................10 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................10 
5.3.4 
Examination of Subgroups ...........................................................................10 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................10 
5.3.6 
Other Considerations ...................................................................................10 
5.4 
Safety Analyses ......................................................................................................10 
5.4.1 
Extent of Exposure .......................................................................................10 
5.4.2 
Adverse Events ............................................................................................11 
5.4.3 
C-SSRS ........................................................................................................12 
5.4.4 
Laboratory Values ........................................................................................12 
5.4.5 
Vital Signs ....................................................................................................13 
5.4.6 
Electrocardiograms ......................................................................................13 
5.4.7 
Safety MRI ...................................................................................................14 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 2 of 25 
 
Page 3 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
5.4.8 
Other Safety Analyses..................................................................................14 
5.5 
Efficacy Analyses ..................................................................................................14 
5.5.1 
Primary Efficacy Analyses ..........................................................................14 
5.5.2 
Secondary Efficacy Analyses ......................................................................14 
5.5.3 
Other Efficacy Analyses ..............................................................................15 
5.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .................................................................................................................15 
5.6.1 
Pharmacokinetic Analyses ...........................................................................15 
5.6.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....15 
5.7 
Other Analyses .......................................................................................................15 
6 
INTERIM ANALYSES ...................................................................................................15 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................16 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................17 
8.1 
Definition of baseline .............................................................................................17 
8.2 
Algorithms for Efficacy Parameters ......................................................................17 
8.3 
Definition of visit windows ...................................................................................21 
8.4 
Definition of duration of treatment and duration of exposure ...............................22 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................22 
10 STATISTICAL SOFTWARE ..........................................................................................22 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................22 
12 REFERENCES ................................................................................................................22 
13 APPENDICES .................................................................................................................23 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....23 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 3 of 25 
 
Page 4 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AChEI 
Acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale - cognitive subscale 
AE 
adverse event 
ApoE 
Apolipoprotein E 
BMI 
body mass index 
BP 
blood pressure 
CBB 
CogState Brief Battery 
C-CASA 
Columbia- classification algorithm of suicide assessment 
CDR 
Clinical Dementia Rating 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
ED 
early discontinuation 
eCRF 
electronic case report form 
FAQ 
functional assessment questionnaire 
FAS 
full analysis set 
INR 
international normalized ratio 
ISLT 
International Shopping List Task 
LLT 
Lower level term 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
mini-mental state examination 
MRI 
magnetic resonance imaging 
OLE 
open-label extension 
PD 
pharmacodynamic 
PT 
Preferred term 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 4 of 25 
 
Page 5 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
Abbreviation 
Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
standard deviation 
SI 
Système International 
SOC 
System organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TLG 
tables, listings, and graphs 
vMRI 
Volumetric magnetic resonance imaging 
WHO DD 
World Health Organization Drug Dictionary 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 5 of 25 
 
Page 6 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
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 from Open-label Extension (OLE) phase 
of study E2609-G000-202. This SAP is based on the protocol amendment 08 and “study” 
indicates OLE phase unless specifically described. 
3.1 
Study Objectives 
3.1.1 
Primary Objective(s) 
• To assess the long-term safety and tolerability of daily dosing with elenbecestat (E2609) 
50 mg in mild cognitive impairment (MCI)/Prodromal subjects and in subjects with mild 
to moderate dementia due to Alzheimer's disease (AD) 
3.1.2 
Secondary Objective(s) 
• To explore the long-term effects of elenbecestat on clinical status by assessment of:  
a. The Mini-Mental State Examination (MMSE) 
b. The Functional Assessment Questionnaire (FAQ; also known as the Functional 
Activities Questionnaire) 
• To explore the long-term effects of elenbecestat on: 
a. Volumetric magnetic resonance imaging (vMRI) including, but not limited to, total 
hippocampal volume, left and right hippocampal volume, whole brain volume, and 
total ventricular volume at 24 and 48 months of treatment in the Extension Phase. 
b. Plasma amyloid at 12, 24, 36, and 48 months of treatment in the Extension Phase 
 
3.2 
Overall Study Design and Plan 
The Extension Phase allows eligible subjects to receive elenbecestat 50 mg for up to 48 months 
(4 years).  
Subjects who are enrolled in the Core Study will have the option to participate in the Extension 
Phase provided that they complete the Core Study (which includes 18 months of double-blind 
treatment and 12 weeks of Follow-up Period) and satisfy the entry criteria for the Extension 
Phase.  Subjects who discontinue from study drug during the Core Study are not eligible to 
participate in the Extension Phase.   
Eligible subjects who choose to participate in the Extension Phase may enter the Extension Phase 
immediately following the completion of Visit 20 (ie, Visit 21 procedures may be completed on 
the same day as Visit 20).  Subjects who are eligible to participate in the Extension Phase but 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 6 of 25 
 
Page 7 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
who do not transition to the Extension Phase on the day of Visit 20 may enter the Extension 
Phase any time within 4 weeks of Visit 20.  The Medical Monitor must be contacted if Visit 21 is 
to occur more than 4 weeks after Visit 20.  For all subjects, assessments performed at V20 may 
serve as baseline values for the Extension Phase (ie, results of assessments conducted at Visit 21) 
with exceptions of laboratory assessments and vital signs, which must be repeated if Visit 21 
occurs more than 10 days from Visit 20.    
During the Extension Phase, subjects will receive open-label elenbecestat 50 mg per day for up 
to 48 months.  Subjects with pending International Normalized Ratio (INR) and serum 
pregnancy test results (females subjects of child bearing potential only) but who are otherwise 
qualified may begin OLE dosing at Visit 21; however, these subjects must discontinue study 
drug treatment immediately if either test result meet the exclusion criteria. 
Safety assessments will be performed as described in Table 14 of the protocol.  Subjects may 
discontinue from study drug for any reason.  Subjects who complete 48 months of the Extension 
Phase treatment or who discontinue the study drug must comply with the Early Discontinuation 
Visit (within 7 days after the last dose of study drug) and the Follow-Up Visits (weeks 4 and 12 
after the last dose of study drug).  
The study will end when the last visit for the last subject has completed the Extension Phase. 
4 
DETERMINATION OF SAMPLE SIZE 
Subjects who complete the Core Study will have the option to participate in the Extension Phase.  
There is no sample size calculation for the Extension Phase.   
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, minimum and maximum.  Categorical variables will be summarized as number 
(percentage) of subjects. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
• Safety endpoints: adverse event (AE), vital sign, electrocardiogram (ECG), physical 
examination, clinical laboratory test, any relevant test of cognitive function to evaluate 
decline, and magnetic resonance imaging (MRI) parameter (microhemorrhage, vasogenic 
edema, and other clinically significant abnormalities). 
5.1.2 
Secondary Endpoints 
Changes from Core Study and Extension Phase baselines in  
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 7 of 25 
 
Page 8 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
• MMSE and FAQ at each visit assessed in the Extension Phase 
• Plasma amyloid measurements at 12, 24, 36, and 48 months of Extension Phase treatment 
• vMRI parameters including, but not limited to, total hippocampal volume, left and right 
hippocampal volume, whole brain volume, and total ventricular volume with up to 24 and 
48 months of Extension Phase treatment 
Due to the termination of the study, only change from Extension Phase baseline will be 
summarized and change from Core Study baseline will not be summarized. Percent change from 
Extension Phase baseline will be summarized if applicable. 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The OLE Safety Analysis Set (OLE-SAS) is the group of subjects who receive at least 1 dose of 
study drug during the OLE Phase.  
The OLE Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 1 dose of 
study drug during the OLE Phase and have baseline and at least 1 postdose efficacy assessment 
during the OLE Phase. 
The OLE pharmacodynamics (PD) Analysis Set is the group of subjects who have baseline and 
at least 1 posttreatment PD measurement in the OLE Phase. 
5.2.2 
Subject Disposition 
The number of subjects screened, the number (percent) of subjects who failed screening, and the 
reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition (OLE phase) electronic case report form (eCRF). 
Study Completion: The number (percent) of enrolled and treated subjects who completed the 
study and who withdrew from the study will be summarized according to the primary reason for 
discontinuation and secondary reason(s) for discontinuation, based on data reported on the 
Subject Disposition (OLE phase) eCRF. The number (percent) will be presented for treatment 
group by core study treatment (placebo and elenbecestat total) and combined total; enrolled, not 
treated, treated, who completed the study, and withdrew from the study. The primary reasons for 
early withdrawal from the study are: AE, lost to follow-up, subject choice, withdrawal of 
consent, pregnancy, study terminated by sponsor, and other. The secondary reasons for early 
withdrawal from the study are: AE, subject choice, and other. 
Completion of Study Treatment: The number (percent) of randomized and treated subjects who 
completed study drug and who discontinued from study drug will be summarized according to 
the primary reason for discontinuation and also according to secondary reason(s) for 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 8 of 25 
 
Page 9 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
discontinuation, based on data reported on both the Subject Disposition  (OLE phase) eCRF and 
Early Discontinuation (ED) from Study Drug (OLE phase) eCRF. The number (percent) will be 
presented for treatment group by core study treatment (placebo and elenbecestat total) and 
combined total; enrolled, not treated, treated, who completed study drug, and discontinued from 
study drug. The primary reasons for early discontinuation from the study drug are: AE, subject 
choice, inadequate therapeutic effect, pregnancy and other. The secondary reasons for early 
discontinuation from the study drug are: AE, subject choice, inadequate therapeutic effect, and 
other. 
5.2.3 
Protocol Deviations 
A listing of subjects with protocol deviations will be provided by subject along with the 
description of the protocol deviation. Protocol deviations will be identified prior to database 
lock. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the OLE-SAS will be summarized by 
treatment group by core study treatment (placebo and elenbecestat total) and combined total 
using descriptive statistics.  Continuous demographic and baseline variables include age, weight, 
body mass index (BMI), Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-
cog14), Clinical Dementia Rating (CDR) Sum of Boxes, MMSE, International Shopping List 
Task (ISLT) z-score (total recall, delayed recall), CogState Brief Battery (CBB) z-score 
(accuracy of one-back memory, accuracy of one-card learning, speed of one-back memory, 
speed of detection, speed of identification), and FAQ; categorical variables include sex, age 
group (≤65 years, age >65 years), race, ethnicity, Apolipoprotein E4 (ApoE4) status (positive or 
negative), prior treatment with Acetylcholinesterase inhibitors (AChEIs) or memantine at OLE 
baseline (no or yes), clinical population (MCI/Prodromal AD, mild to moderate AD) at screening 
in Core Study, and CDR global score  
 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the case report form (CRF) will be coded to an 
11-digit code using the World Health Organization Drug Dictionary (WHO DD) (May 2014 or 
higher).  All medications will be presented in subject data listings. 
5.2.6 
Treatment Compliance 
Percent compliance will be calculated as follows: 
Compliance= 
 
Total number of tablets dispensed –  Total number of tablets returned
Planned Total number of tablets to be taken
× 100% 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 9 of 25 
 
Page 10 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
                                   
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Since the primary objective of this study is about safety and tolerability, no multiplicity 
adjustment will be applied. 
5.3.4 
Examination of Subgroups 
Not applicable.  
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
If any item is missing within the MMSE, and FAQ, then their respective total scores will be 
missing. 
For plasma Ab(1-x), values >upper limit of quantification (ULOQ) or < lower limit of 
quantification (LLOQ) will be imputed using ULOQ or LLOQ respectively. 
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Safety Analyses 
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be based 
on OLE-SAS.  The incidence of AEs, out-of-normal-range laboratory safety test variables, 
abnormal ECG findings, out-of-range vital signs, suicidality (Columbia Suicide Severity Rating 
Scale(C-SSRS)), and changes from baseline in laboratory safety test variables, ECGs, safety 
MRI, vital sign measurements, and cognitive decline assessment such as MMSE will be 
summarized by using descriptive statistics.  The OLE baseline is used for all safety analyses. 
5.4.1 
Extent of Exposure 
The extent of exposure to study drug will be summarized by categories of cumulative months as 
well as by categories of duration of exposure in 3-month intervals. The number and percent of 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 10 of 25 
 
Page 11 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
subjects for each exposure category will be presented for treatment group by core study 
treatment (placebo and elenbecestat total) and combined total. Duration of exposure is the 
number of months between the date the subject received the first dose of OLE study drug and the 
date the subject received the last dose of OLE study drug and will be summarized using 
descriptive statistics as continuous variable for treatment group by core study treatment (placebo 
and elenbecestat total) and combined total. Overall exposure (number of subject months) is 
defined as summation over all subjects’ exposure durations in the OLE and will be summarized 
for treatment group by core study treatment (placebo and elenbecestat total) and combined total. 
5.4.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 22.0 or higher) lower level 
term (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 
in OLE, having been absent at pretreatment (Baseline) in OLE or  
• Reemerged during treatment in OLE, having been present at pretreatment (Baseline) in OLE 
but stopped before treatment in OLE, or  
• Worsened in severity during treatment in OLE relative to the pretreatment state, when the AE 
was continuous. 
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized for treatment group by core study treatment (placebo and 
elenbecestat total) and combined total. 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 TEAEs 
will also be summarized by relationship to study drug (Yes [related] and No [not related]).  
A subject data listing of all AEs leading to death will be provided. 
The number (percent) of subjects with treatment-emergent serious adverse events (SAEs) will be 
summarized by MedDRA SOC and PT for treatment group by core study treatment (placebo and 
elenbecestat total) and combined total. A subject data listing of all SAEs will be provided. 
The number (percent) of subjects with TEAEs leading to discontinuation from study drug will be 
summarized by MedDRA SOC and PT for treatment group by core study treatment (placebo and 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 11 of 25 
 
Page 12 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
elenbecestat total) and combined total. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided. 
The number (percent) of subjects with TEAEs with specific interest will be summarized by 
MedDRA SOC and PT for treatment group by core study assignment (placebo and elenbecestat 
total) and combined total. 
The number (percent) of subjects with non-serious TEAEs will be summarized by MedDRA 
SOC and PT for treatment group by core study assignment (placebo and elenbecestat total) and 
combined total.  
5.4.3 
C-SSRS 
The C-SSRS responses will be mapped to Columbia- classification algorithm of suicide 
assessment (C-CASA). The incidence of new or worsening suicidal ideation or suicidal behavior 
will be summarized for treatment group by core study treatment (placebo and elenbecestat total) 
and combined total. The clinical assessment of suicidal thinking and behavior will also be 
summarized for treatment group by core study treatment (placebo and elenbecestat total) and 
combined total. Categorical variables will be summarized by number (percentage) of subjects. 
 
5.4.4 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate. For 
all quantitative parameters, the actual value and the change from baseline to each post-baseline 
visit will be summarized by visit for treatment group by core study treatment (placebo and 
elenbecestat total) and combined total using descriptive statistics. The end of treatment visit and 
12 week Follow-up visit are also included, as appropriate. Qualitative parameters will be 
summarized using frequencies (number and percent of subjects), and changes from baseline to 
each post-baseline visit will be reported using shift tables. Percentages will be based on the 
number of subjects with both non-missing baseline and relevant post-baseline results.  
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range. Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each post-baseline visit and at the end of treatment visit and 12 week Follow-up visit. 
The Sponsor’s Grading for Laboratory Values (Appendix 13.1) presents the criteria that will be 
used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV). Except for phosphate, a TEMAV is defined as a post-baseline value with an increase 
from baseline to a grade of 2 or higher. For phosphate, a TEMAV is defined as a post-baseline 
value with an increase from baseline to a grade of 3 or higher. The incidence of TEMAVs will be 
summarized for treatment group by core study treatment (placebo and elenbecestat total) and 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 12 of 25 
 
Page 13 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
combined total. When displaying the incidence of TEMAVs, each subject will be counted once 
in the laboratory parameter high and low categories, as applicable. 
Lymphocyte subset parameters (ie, CD4 [T helper cells], CD8 [cytotoxic T cells], CD19 [B 
cells], CD16/CD56 [natural killer cells] and CD14 [macrophages], and regulatory T cells) will be 
summarized in the same manner as other laboratory parameters.  
5.4.5 
Vital Signs 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic blood pressure (BP), 
pulse, respiratory rate, temperature, weight), and changes from baseline will be presented by visit 
for treatment group by core study treatment (placebo and elenbecestat total) and combined total. 
In addition, frequency counts of clinically notable vital signs will be summarized for treatment 
group by core study treatment (placebo and elenbecestat total) and combined total. Table 1 
presents the clinical notable ranges. 
Table 1: Clinical Notable Ranges for Vital Signs 
Vital Sign 
Criterion for Low 
Criterion for High 
Pulse (bpm) 
< 40 
> 120 
Temperature (°C) 
< 36 
> 38 
Weight (kg) 
< 45  
> 100 
Systolic BP 
< 90 
> 160 
Diastolic BP 
< 50 
> 100 
5.4.6 
Electrocardiograms 
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
for treatment group by core study treatment (placebo and elenbecestat total) and combined total. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; abnormal, clinically significant) to each post-baseline visit 
and to the end of treatment visit and the 12 week Follow-up visit. 
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in QTcF during the treatment period will be summarized. Clinically abnormal ECG results 
in QTcF will be categorized as follows: 
Absolute QTcF interval prolongation: 
• QTcF interval >450 msec 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 13 of 25 
 
Page 14 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
• QTcF interval >480 mse 
• QTcF interval >500 msec 
Change from baseline in QTcF interval: 
• QTcF interval increases from baseline >30 msec 
• QTcF interval increases from baseline >60 msec 
5.4.7 
Safety MRI 
Vasogenic Edema and white matter disease will be summarized by visit for treatment group by 
core study treatment (placebo and elenbecestat total) and combined total. Shift table for the total 
number of microhemorrages will be presented by visit for treatment group by core study 
treatment (placebo and elenbecestat total) and combined total. Other abnormalities will be 
presented in subject data listing. 
5.4.8 
Other Safety Analyses 
Comprehensive neurological examination results will be summarized by visit for treatment group 
by core study treatment (placebo and elenbecestat total) and combined total. 
Dermatology findings will be presented in subject data listing. 
Cognitive decline will be assessed as a safety assessment, in addition to efficacy assessments. 
Cognitive assessments will include MMSE. 
5.5 
Efficacy Analyses 
There is no primary efficacy analysis for this study. Secondary analyses will be based on OLE-
FAS as specified in Section 5.2.1.  The analyses using OLE baseline are summarized by 
treatment group by core study treatment (placebo, elenbecestat 50 mg R, elenbecestat 50 mg 
Total) and combined total. Elenbecestat 50 mg R group are the subjects initially randomized to 
50 mg group in Core Study. Elenbecestat 50 mg Total group are the subjects ever exposure to 50 
mg in Core Study. 
5.5.1 
Primary Efficacy Analyses 
There is no primary efficacy endpoint. 
5.5.2 
Secondary Efficacy Analyses 
The secondary efficacy endpoints in this SAP are:  
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 14 of 25 
 
Page 15 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
• Change from OLE baseline in MMSE and FAQ scores 
• Change / percent change from OLE baseline in total hippocampal volume, left and right 
hippocampal volume, whole brain volume, and total ventricular volume with up to 24 and 
48 months as measured by vMRI 
The actual value and change (percent change, if applicable) from baseline will be summarized 
using descriptive statistics for OLE baseline. Due to the termination of the study, the summary 
statistics will not be presented graphically.  
Due to the termination of the study, the relationship between efficacy endpoints and biomarker 
endpoints will not be explored using correlation analysis. 
 
5.5.3 
Other Efficacy Analyses 
No other efficacy analyses are planned for this study 
5.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
The OLE PD Analysis Set will be used for the summaries and analyses of PD biomarkers. The 
same summary groups as for efficacy are used for PD analyses. 
5.6.1 
Pharmacokinetic Analyses 
Not applicable. 
5.6.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
The secondary endpoint from PD marker in this SAP is:  
• Percent Change from baseline in plasma amyloid measurements 
The actual value and percent change from OLE baseline will be summarized using descriptive 
statistics for OLE baseline. Due to the termination of the study, the summary statistics will not be 
presented graphically. 
5.7 
Other Analyses 
No other analyses are planned. 
6 
INTERIM ANALYSES 
No interim analyses in OLE phase. 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 15 of 25 
 
Page 16 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
7 
CHANGES IN THE PLANNED ANALYSES 
Due to the termination of the study, the following analyses, as described in the protocol, will not 
be performed. 
• Summary statistics of change from Core Study baseline in MMSE, FAQ, vMRI 
parameters, and PD biomarkers 
• Figures of change from baseline in MMSE, FAQ, vMRI parameters, and PD biomarkers 
• Correlation analysis for the relationship between efficacy endpoints and biomarker 
endpoints 
 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 16 of 25 
 
Page 17 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Definition of baseline 
The OLE baseline value is defined as the most recent value reported just before first dosing in 
OLE (for safety, efficacy and PD). 
8.2 
Algorithms for Efficacy Parameters 
This section describes each efficacy parameter, in particular, the algorithms and missing data 
handling procedure to derive the totals scores if applicable. 
 
FAQ: The Functional Assessment Questionnaire (FAQ) is composed of 10 activities. Each 
activity is rated as 0 = Normal, 1 = Has difficulty but does by self, 2 = Requires assistance, 3 = 
Dependent, 8 = Not Applicable.  The Total Score is the sum of the 10 activities.  If any activity is 
missing then the Total Score is missing.  Activities marked as “Not Applicable”, are not use in 
the computation of the Total Score.  However, in order to account for “Not Applicable” 
activity(s), the Total Score is weighted as follows; 
Total Score = Total Score x 30 / (30 minus 3 times the number of activities marked “Not 
Applicable”)  
ISLT: The International Shopping List Task (ISLT) is a verbal learning and episodic memory 
test assessing both immediate and delayed recall. Number of correct responses is used as the 
score in both tests and transformed to Z-score, respectively. 
CBB: The CogState Brief Battery (CBB) is a computer-based battery comprising 4 cognitive 
tests: 
   Detection – a simple reaction time test. Speed of response is the measure. 
   Identification – a simple choice reaction time test. Speed of response is the measure. 
   One Card Back – a simple working memory test. Accuracy of response is the measure. 
   One Card Learning – a visual learning and memory test. Accuracy of response is the measure. 
CDR:  The Clinical Dementia Rating (CDR) scale is a clinical global rating scale requiring the 
interviewing of both the subject and an informant who knows and has contact with the subject. 
The CDR is a clinician-directed assessment of both cognition and function, and is intended to 
capture the state and therefore the disease stage of the individual.  The CDR assesses 6 domains 
of subject function; memory, orientation, judgment and problem solving, community affairs, 
home and hobbies, and personal care. Each of these items has a maximum possible score of 3 
points and the total score is a sum of the item scores (sum of boxes) giving a total possible score 
of 0 to 18 with higher scores indicating more impairment. 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 17 of 25 
 
Page 18 of 26


 
Eisai 
E2609-G000-202  
Open-Label Extension Phase  
(Statistical Analysis Plan) 
 
MMSE:  The Mini Mental State Examination (MMSE) is a cognitive instrument commonly used 
for screening purposes, for staging of disease severity and is often measured longitudinally in 
AD clinical studies to follow disease progression and treatment effects. MMSE is composed of 
30 questions grouped into domains.  For each of the MMSE domains add the correct responses.  
If a domain has missing data then the domain is missing.  From the domains compute the six 
items as show in Table 3.  If any domain is missing then the item is missing.  The MMSE Total 
Score (range 0 to 30) = sum of the six items.  If any item score is missing then the Total Score is 
missing. 
Table 3:   MMSE Domains and Items 
Domain 
Score 
Range 
Item 
Score 
Range 
1. Orientation to Time 
0 to 5 
1. Orientation to Time 
0 to 5 
2. Orientation to Place 
0 to 5 
2. Orientation to Place 
0 to 5 
3. Registration 
0 to 3 
3. Registration 
0 to 3 
4. Attention and 
Calculationa  
0 to 5 
4. Attention and Calculation 
0 to 5 
5. Recall 
0 to 3 
5. Recall 
0 to 3 
6. Naming 
0 to 2 
6. Language (Sum of Naming, 
Repetition, Comprehension, 
Reading, Writing, and Drawing) 
0 to 9 
7. Repetition 
0 to 1 
 
 
8. Comprehension 
0 to 3 
 
 
9. Reading 
0 to 1 
 
 
10. Writing 
0 to 1 
 
 
11. Drawing 
0 to 1 
 
 
 
 
Total Score 
0 to 30 
a Spell WORLD Forward, then Backward score is only used if Attention and Calculation score is not 
available 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 18 of 25 
 
Page 19 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
ADAS-cog14:  The Alzheimer’s Disease Assessment Scale - Cognitive subscale (14 items) 
(ADAS-cog14) is composed of 14 items, see Table 4. 
Table 4: ADAS-cog14 Items and Algorithm for derivation of Item Scores and Total Score 
Item 
Algorithm 
Handling Missing 
Data 
Score 
Range 
1. Word Recall 
Total the number of “No” responses for 
each trial.  The subscore is the sum the 
scores from trials 1, 2, and 3, divide by 3. 
If a trial is missing or 
partially done then 
trial score is missing.  
If a trial score is 
missing then the 
subscore is missing  
0 to 10 
2. Commands 
Total the number of “No” responses from 
the 5 tasks 
If any task is missing 
then the subscore is 
missing 
0 to 5 
3. Constructional Praxis 
Count the number of “No” responses.  The 
subscore is 
0 = all 4 drawings correct 
1= 1 figure drawn incorrectly 
2= 2 figures drawn incorrectly 
3= 3 figures drawn incorrectly 
4= 4 figures drawn incorrectly 
5= no  figures drawn, scribbles, parts of 
forms  
If any task is missing 
then the subscore is 
missing 
0 to 5 
4. Delayed Word-Recall 
Total the number of “No” responses. 
If any response is 
missing then subscore 
is missing 
0 to 10 
5. Naming Objects / 
Fingers 
Total the number of “No” responses.  The 
subscore is  
0= 0-2 “no” responses 
1= 3-5 “no” responses 
2= 6-8 “no” responses 
3= 9-11 “no” responses 
4= 12-14 “no” responses 
5= 15-17 “no” responses 
If any response is 
missing then subscore 
is missing 
0 to 5 
6. Ideational Praxis 
Total the number of “No” responses.   
If any response is 
missing then subscore 
is missing 
0 to 5 
7. Orientation 
Total the number of “No” responses.   
If any response is 
missing then subscore 
is missing 
0 to 8 
8. Word Recognition 
For each trial, total the number of “1” 
responses.   If the total is 12 or less, then 
the trial score = total.  If the total is > 12 
then trial score=12.  The subscore is the 
sum the scores from trials 1, 2, and 3, 
divide by 3. 
If a trial is missing or 
partially done then 
trial score is missing.  
If a trial score is 
missing then the 
subscore is missing  
0 to 12 
9. Remembering Test 
The subscore is  
If the response is 
0 to 5 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 19 of 25 
 
Page 20 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
Instructions 
0= None, 1= Very Mild, 2= Mild, 3= 
Moderate,  
4= Moderately Severe, 5= Severe 
missing then subscore 
is missing 
10. Comprehension 
The subscore is  
0= None, 1= Very Mild, 2= Mild, 3= 
Moderate,  
4= Moderately Severe, 5= Severe 
If the response is 
missing then subscore 
is missing 
0 to 5 
11. Word Finding 
Difficulty 
The subscore is  
0= None, 1= Very Mild, 2= Mild, 3= 
Moderate,  
4= Moderately Severe, 5= Severe 
If the response is 
missing then subscore 
is missing 
0 to 5 
12. Spoken Language 
Ability 
The subscore is  
0= None, 1= Very Mild, 2= Mild, 3= 
Moderate,  
4= Moderately Severe, 5= Severe 
If the response is 
missing then subscore 
is missing 
0 to 5 
13. Executive Function 
(Maze) 
The subscore is based on the total number 
of seconds to complete the task and/or 
whenever the task was stopped due to 2 
errors being made, as follows; 
 
0 = 0-30 seconds 
1 =  31-60 seconds 
2 = 61 – 90 seconds 
3 = 91 – 120 seconds 
4 = 121-239 seconds 
5 = 240 seconds or at least 2 errors  
If the response is 
missing then the 
subscore is missing 
0 to 5 
14. Number Cancellation 
Adjusted Score = Total # correct targets 
crossed off minus Total # incorrect targets 
crossed off minus Total # times reminded 
of task.  Then use Adjusted Score to 
determine the subscore as follows; 
 
     Adjusted Score           Subscore 
            ≥23                  =      0 
           18-22                =      1 
           13-17                =      2 
           9-12                  =      3 
           5-8                    =      4 
           ≤4                     =      5 
If any component of 
the adjusted score is 
missing then the 
subscore is missing  
0 to 5 
Total Score 
Total Score = sum of the subscores above 
If any subscore is 
missing then Total 
Score is missing 
0 to 90 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 20 of 25 
 
Page 21 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
8.3 
Definition of visit windows 
The protocol specified visits/weeks and corresponding time windows used for visit-wise 
analyses are presented in terms of days relative to the first dose in the OLE.  
Different assessments may have different visit schedules. A general rule for determining a 
time window for each scheduled visit is to split the two consecutive scheduled visits in the 
middle point of the two consecutive visits. For example, the time window for visit X is from 
the middle point between visit (X-1) and X (exclusive) to the middle point between visit X 
and (X+1) (inclusive). The time window for the first post-baseline visit is from the next day 
of the first dose. . The details will be specified in the programming specification.  
In addition, the following visits will be assigned separately (for MMSE, FAQ, and safety 
endpoint) if last dose date is not missing.  
• Last on treatment: the last post-baseline assessment on or before last dose date. 
• End of treatment: the earliest assessment on or after last dose date and before last 
dose date + 56 days (inclusive) 
• 12 week Follow-up: the closest assessment to last dose date + 84 days after last dose 
date + 57 days (inclusive)  
The assessments after last dose date + 8 days (inclusive) will not be included in the visit-wise 
analyses except end of treatment visit and 12 week Follow-up visit (the analysis flag should 
not be “Y”). If last dose date is missing, the assessment at early discontinuation from study 
drug, follow-up visits and unscheduled visits on or after early discontinuation from study 
drug or follow-up visits will not be included in the visit-wise analyses. 
For biomarker endpoints, the following allowance after last dose date will be used. The 
assessments out of each allowance will not be included in the visit-wise analyses. 
• Plasma Ab(1-x): last dose days + 5 days (inclusive) 
• vMRI: no limitation (all assessments will be included) 
If last dose date is missing, the assessment at early discontinuation from study drug, follow-
up visits and unscheduled visits on or after early discontinuation from study drug or follow-
up visits will not be included in the visit-wise analyses for Plasma Ab(1-x).  
If there are multiple assessments for one analysis visit, the following rules will be applied in 
order to select one assessment. 
1. Pick the closest assessment to the target day 
2. Pick the assessment at scheduled visit than unscheduled visit 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 21 of 25 
 
Page 22 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
3. Pick the earliest assessment within the same visit (day) 
8.4 Definition of duration of treatment and duration of exposure 
The duration of treatment will be calculated using the following equation. 
• Duration of treatment = date of last dose of study drug – date of first dose of study 
drug + 1 
The duration of exposure will be calculated using the following equation. 
• Duration of exposure = date of last dose of study drug – date of first dose of study 
drug + 1 
If drug interruption occurs, then the drug interruption duration will be subtracted to calculate 
duration of exposure. For both duration, if the date of last dose of study drug is missing, the 
date of early discontinuation from study drug will be used instead. If the date of early 
discontinuation from study drug is also missing, the date of completion or discontinuation 
will be used instead. 
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS v 9.3 or later. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs (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 
No references. 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 22 of 25 
 
Page 23 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
13 APPENDICES 
13.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results  
The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, 
Appendix 1. 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
< LLN – 10.0 g/dL 
< LLN – 100 g/L 
< LLN – 6.2 mmol/L 
< 10.0 – 8.0 g/dL 
< 100 – 80 g/L 
< 6.2 – 4.9 mmol/L  
< 8.0 g/dL 
< 80 g/L 
< 4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
< LLN – 3.0 x 109/L 
< LLN – 3000/mm3  
< 3.0 – 2.0 x 109/L 
< 3000 – 2000/mm3  
< 2.0 – 1.0 x 109/L 
< 2000 – 1000/mm3  
< 1.0 x 109/L 
< 1000/mm3  
Lymphocytes  
< LLN – 800/mm3  
< LLN – 0.8 x 109/L 
< 800 – 500/mm3 
< 0.8 – 0.5 x 109/L 
< 500 – 200/mm3  
< 0.5 – 0.2 x 109/L 
< 200/mm3 
< 0.2 x 109/L 
Neutrophils  
< LLN – 1.5 x 109/L 
< LLN – 1500/mm3  
< 1.5 – 1.0 x 109/L 
< 1500 – 1000/mm3 
< 1.0 – 0.5 x 109/L 
< 1000 – 500/mm3  
< 0.5 x 109/L 
< 500/mm3  
Platelets 
< LLN – 75.0 x 109/L 
< LLN – 75,000/mm3  
< 75.0 – 50.0 x 109/L 
< 75,000 – 50,000/mm3  
< 50.0 – 25.0 x 109/L 
< 50,000 – 25,000/mm3 
< 25.0 x 109/L 
< 25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
< LLN – 3 g/dL 
< LLN – 30 g/L 
< 3 – 2 g/dL 
< 30 – 20 g/L 
< 2 g/dL 
< 20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
ALT 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
AST 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Bicarbonate, serum-low  
< LLN – 16 mmol/L 
< 16 – 11 mmol/L 
<11 – 8 mmol/L 
< 8 mmol/L  
Bilirubin (hyperbilirubinemia) 
> ULN – 1.5 x ULN  
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN  
> 10.0 x ULN 
Calcium, serum-low (hypocalcemia)  
< LLN – 8.0 mg/dL 
< LLN – 2.0 mmol/L 
< 8.0 – 7.0 mg/dL 
< 2.0 – 1.75 mmol/L 
< 7.0 – 6.0 mg/dL 
< 1.75 – 1.5 mmol/L 
< 6.0 mg/dL 
< 1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
> ULN – 11.5 mg/dL 
> ULN – 2.9 mmol/L 
> 11.5 – 12.5 mg/dL 
> 2.9 – 3.1 mmol/L 
> 12.5 – 13.5 mg/dL 
> 3.1 – 3.4 mmol/L 
> 13.5 mg/dL 
> 3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
> ULN – 300 mg/dL 
> ULN – 7.75 mmol/L  
> 300 – 400 mg/dL 
> 7.75 – 10.34 mmol/L  
> 400 – 500 mg/dL 
> 10.34 – 12.92 mmol/L  
> 500 mg/dL 
> 12.92 mmol/L  
Creatinine 
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 6.0 x ULN 
> 6.0 x ULN 
GGT (γ-Glutamyl transpeptidase)  
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
> ULN – 160 mg/dL 
> ULN – 8.9 mmol/L  
Fasting glucose value: 
> 160 – 250 mg/dL 
> 8.9 – 13.9 mmol/L  
> 250 – 500 mg/dL; 
> 13.9 – 27.8 mmol/L; 
hospitalization indicated 
> 500 mg/dL; 
> 27.8 mmol/L; 
life-threatening 
consequences  
Glucose, serum-low (hypoglycemia) 
< LLN – 55 mg/dL 
< LLN – 3.0 mmol/L 
< 55 – 40 mg/dL 
< 3.0 – 2.2 mmol/L 
< 40 – 30 mg/dL 
< 2.2 – 1.7 mmol/L 
< 30 mg/dL 
< 1.7 mmol/L 
life-threatening 
consequences; 
seizures 
Phosphate, serum-low 
(hypophosphatemia)  
< LLN – 2.5 mg/dL 
< LLN – 0.8 mmol/L 
< 2.5 – 2.0 mg/dL 
< 0.8 – 0.6 mmol/L 
< 2.0 – 1.0 mg/dL 
< 0.6 – 0.3 mmol/L 
< 1.0 mg/dL 
< 0.3 mmol/L 
life-threatening 
consequences 
Potassium, serum-high (hyperkalemia) > ULN – 5.5 mmol/L  
> 5.5 – 6.0 mmol/L 
> 6.0 – 7.0 mmol/L 
hospitalization indicated 
> 7.0 mmol/L 
life-threatening 
consequences 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 23 of 25 
 
Page 24 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium, serum-low (hypokalemia)  
< LLN – 3.0 mmol/L 
< LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
< 3.0 – 2.5 mmol/L 
hospitalization indicated 
< 2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
> ULN – 150 mmol/L 
> 150 – 155 mmol/L 
> 155 – 160 mmol/L 
hospitalization indicated 
> 160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
< LLN – 130 mmol/L 
N/A 
< 130 – 120 mmol/L 
< 120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
> 300 – 500 mg/dL 
> 3.42 – 5.7 mmol/L  
> 500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
> 1000 mg/dL 
> 11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L without 
physiologic 
consequences  
N/A 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L with 
physiologic 
consequences  
> 10 mg/dL 
> 0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 24 of 25 
 
Page 25 of 26


Statistical Analysis Plan 
E2609-G000-202 OLE Phase 
 
 
SIGNATURE PAGE 
Author:   
 
 
 
[electronic signature in eDMS] 
 
 
 
Neurology Business Group, Eisai Inc. 
 
Date 
Approval: 
 
 
 
[electronic signature in eDMS] 
 
 
 
 
Neurology Business Group, Eisai Inc. 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
 
Neurology Business Group, Eisai Inc. 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
 
Neurology Business Group, Eisai Ltd. 
 
Date 
 
 
Eisai 
FINAL (Version 1.0):  18Feb2020 
Confidential 
Page 25 of 25 
 
Page 26 of 26
PPD
PPD
PPD
PPD